Part 1: Physiology 448
Morphological development of the lung 448
Factors influencing lung growth and development 448
Pulmonary circulation 450
Cardiorespiratory adaptation at birth 450
Aeration of the lungs at birth 450
Changes in lung mechanics after birth 451
Circulatory changes at birth 451
Postnatal function 451
Gas exchange in the neonatal lung 452
Gas transport in the blood 453
Regulation of breathing 454
Responses to changes in oxygen tension 455
Response to carbon dioxide/acidosis 455
Respiratory reflexes 456
The Hering–Breuer reflexes 456
Head’s paradoxical reflex 456
The intercostal phrenic inhibitory reflex 456
Irritant reflexes 457
Upper airway reflexes 457
Lung mechanics 457
Origins of surfactant 459
Surfactant protein A 460
Surfactant protein B 460
Surfactant protein C 461
Surfactant protein D 461
Factors affecting surfactant maturation 462
Surfactant physical properties and functions 463
Inhibition of surface activity of surfactant by proteins 463
Assessment of surfactant maturity 463
Part 2: Acute respiratory disease 468
Respiratory distress syndrome 468
Prevention of respiratory distress syndrome 473
Clinical features of respiratory distress syndrome 476
Differential diagnosis 477
Transient tachypnoea of the newborn 485
Differential diagnosis 486
Minimal respiratory disease 486
Clinical features 486
Differential diagnosis 486
Pulmonary airleaks 486
Pulmonary interstitial emphysema 490
Systemic air embolism 494
Subcutaneous emphysema 494
Persistent pulmonary hypertension of the newborn 495
Definition and classification 495
Clinical features 497
Differential diagnosis 497
Monitoring babies with persistent pulmonary hypertension of the newborn 500
Weaning the baby with persistent pulmonary hypertension of the newborn off therapy 500
Natural history and prognosis 501
Meconium aspiration syndrome 501
Clinical signs 503
Differential diagnosis 504
Aspiration of amniotic fluid 506
Aspiration of fluid at delivery 506
Other aspiration syndromes 507
Pulmonary haemorrhage 509
Clinical features 510
Differential diagnosis 510
Asphyxial lung disease/acute respiratory distress syndrome 512
Clinical features 512
Differential diagnosis 512
Pleural effusions 513
Management of neonatal respiratory failure 516
Part 3: Chronic lung disease 552
Bronchopulmonary dysplasia 552
Clinical presentation 554
Differential diagnosis of bronchopulmonary dysplasia 556
Other forms of chronic lung disease 564
Wilson–Mikity syndrome 564
Part 4: Apnoea and bradycardia 571
Incidence of clinical apnoea 571
Types of apnoea 572
Mechanisms of apnoea 572
Factors involved in apnoea 574
Periodic breathing, sleep state and diaphragmatic fatigue 574
Genetic predisposition 575
Central nervous system disorders 575
Environmental temperature 575
Gastro-oesophageal reflux 575
Apnoea and bottle feeding 575
Patent ductus arteriosus 575
Investigation of apnoea 576
Treatment of apnoea of prematurity 576
Treatment of individual episodes of apnoea 577
Other therapeutic options 577
Stopping treatment, predischarge monitoring and discharge home 577
Home monitoring 578
Part 5: Malformations of the lower respiratory tract 581
Pulmonary agenesis 581
Pulmonary hypoplasia 581
Primary pulmonary hypoplasia 581
Secondary pulmonary hypoplasia 581
Clinical features 581
Small-chest syndromes 583
Congenital cystic adenomatoid malformation 585
Congenital lung cysts 587
Pulmonary sequestration 587
Congenital pulmonary lymphangiectasis 588
Pulmonary alveolar proteinosis (congenital alveolar proteinosis) 588
Congenital lobar emphysema 588
Ciliary abnormalities 589
Part 6: Diaphragmatic hernia 593
Congenital posterolateral diaphragmatic hernia 593
Anatomy and pathophysiology 594
Clinical features 595
Prediction of prognosis 598
Outcome in congenital diaphragmatic hernia 599
Anterior diaphragmatic hernias 600
Diaphragmatic eventration 601
Part 7: Airway problems 604
Development of the nose, larynx and trachea and lungs 604
Higher upper airway obstruction 604
Choanal atresia 604
Oropharyngeal airway obstruction and stertor 605
Management of oropharyngeal upper airway obstruction 605
Prognosis of high upper airway obstruction 606
Laryngotracheal airway obstruction 606
Assessment of airway obstruction and stridor 606
Investigations for stridor 606
Management of stridor and laryngotracheal airway obstruction 606
Airway endoscopy 606
Care of the intubated baby 607
Laryngotracheal airway obstruction: conditions and management 609
Airway cysts and webs 609
Vocal cord paralysis 609
Congenital posterior laryngeal cleft 610
Subglottic stenosis 610
Subglottic haemangioma 611
Vascular compression (rings and slings) 612
Congenital microtrachea 612
Tracheomalacia, bronchomalacia 612
Bronchoscopy for atelectasis and air trapping 613
Antenatal airway obstruction and EXIT 615
This chapter reviews the growth of the respiratory system before and after birth, the mechanisms responsible for the production and clearance of lung fluid, how the healthy infant achieves an expanded air-filled lung, the fetal and postnatal development of respiratory control and the development and function of surfactant and the surfactant proteins.
Morphological development of the lung
The primary goal of lung development is to create a large gas exchange area with a thin air–blood barrier. This is achieved by branching of the airways to form the conducting and proximal respiratory airways and by septation to subdivide the airspaces into alveoli ( ).
There are four major stages of lung development:
6–17 weeks: pseudoglandular
17–26 weeks: canalicular
27 weeks to term: alveolar.
The nerves of the lung develop from neural crest cells and migrate via the vagus nerve to the future trachea and lung; there is then progressive extension of the nerve supply ( ). The human fetal lung originates in the 3-week-old embryo as a ventral diverticulum that arises from the caudal end of the laryngotracheal groove of the foregut. The commitment of the foregut endoderm cell to form the lung bud is dependent on the transcription factor, hepatocyte nuclear factor 3-beta ( ). The lung primordium divides into the right and left lung buds and then there is a repetitive process of invasion of the new buds into the surrounding mesenchyme, formation and elongation of the airway tubes and their division to form new airway buds ( ). Fibroblast growth factor-10 (FGF-10)-stimulated sonic hedgehog (Shh) production in the epithelium of the lung bud and increasing expression of Shh and bone morphogenetic protein 4 (BMP4) lateralises FGF-10 activity, which induces outgrowth of new end buds ( ). The bronchial tree is developed by the 16th week of gestation. Gli proteins are essential for lung-branching morphogenesis ( ). During the canalicular stage of development, there is continued branching of respiratory bronchioles, vascularisation of the terminal tubules and thinning of the airway epithelium. Arteries and veins develop alongside the respiratory airways. Towards the end of the canalicular stage (24 weeks), pulmonary gas exchange becomes theoretically possible. By 20–22 weeks of gestation, both type I and type II pneumocytes can be identified. Type I cells are flattened and form over 90% of the gas-exchanging surface of the mature lung. The cuboidal type II cells have a secretory function, and, from 24 weeks, osmiophilic lamellar bodies containing surfactant can be identified.
From 24 weeks to term, further terminal branching occurs, with the development of saccules. New tissue ridges are lifted off the existing primary septa and grow in a centripetal direction into the airspaces. These secondary septa subdivide the sacculi into smaller units, the alveoli ( ). During this period, a capillary network forms around each saccule. A variety of growth factors and their receptors as well as extracellular matrix proteins are involved in the angiogenic process and may also be involved in branching and septation ( Table 27.1 ) ( ). For example, vascular endothelial growth factor (VEGF-α) is expressed by respiratory epithelial cells, stimulating pulmonary vasculogenesis mediated via paracrine signalling to receptors expressed by progenitor cells in the mesenchyme ( ); inhibition of VEGF signalling using a blocker Su-5416, either before or after birth, resulted in reduced vascularisation and alveolarisation ( ).
|PDGF-A||↓ Branching||↓ Alveolarisation|
|PDGF-B||Branching normal but ↓ lung growth|
|VEGF||↓ Branching||↓ Alveolarisation|
|TGF-β||↑ Branching||Emphysema in adults|
|Bmp-4||Mice die before branching|
Although alveoli begin to appear as shallow indentations at about 32 weeks of gestation, most alveolar development occurs postterm. The lung grows postnatally mainly by an increase in alveolar number, and, by 4 years of age, the adult number of alveoli is present ( ). The subsequent increase in lung volume and surface area is due to an increase in alveolar size. In the first 5 years, there is little elastin in the alveolar walls, which only extends around the alveolar walls by 18 years ( ); the early ‘relative’ deficiency of elastin may facilitate the increase in size of the alveoli in the growing lung. There is a two- to threefold increase in diameter and length of airways between birth and adulthood ( ). The amount of bronchial smooth muscle relative to airway size increases between birth and adulthood; the increase in the first weeks after birth is particularly rapid.
Factors influencing lung growth and development
Abnormal lung growth can be the result of inadequate space, or reduction in either fetal breathing or amniotic fluid volume. The time of onset of the insult determines which structures are affected. Prior to 16 weeks of gestation, branching of the airways is impaired permanently, which will also reduce the potential for the number of alveoli. An insult occurring later affects the number of alveoli. Space restriction can be due to an abnormality extrinsic to the lung, for example congenital diaphragmatic hernia, pleural effusion or asphyxiating thoracic dystrophy, or intrinsic to the lung, for example cystic adenomatoid malformation. Other factors influencing lung growth and development include malnutrition, particularly vitamin A deficiency ( ), maternal smoking ( ) and glucocorticoid administration ( ).
Fetal breathing movements
Phrenic nerve or cervical cord resections which abolish fetal breathing movements (FBMs) are associated with arrest of lung growth. Fetal breathing is dependent on normal diaphragmatic function and pulmonary hypoplasia in newborns occurs with generalised neuromuscular disorders, isolated phrenic nerve agenesis and diaphragmatic amyoplasia. During periods of FBM, rhythmical contractions of the diaphragm slow the loss of lung liquid and help to maintain lung expansion when the upper airway resistance is reduced; this may be the mechanism by which FBMs preserve lung growth.
Fetal lung liquid
In fetal life, work in animal models has demonstrated that the lung is filled with liquid, increasing from 4–6 ml/kg bodyweight at midgestation to about 20 ml/kg near term. The hourly rate of production is initially 2 ml/kg, increasing to 5 ml/kg at term. Fetal lung liquid contributes one-third to one-half to the daily turnover of amniotic fluid. Compared with either amniotic fluid or plasma, lung liquid has a high chloride but low bicarbonate and protein concentration. The dominant force mediating lung liquid secretion is the secondary active transport of chloride ions from the interstitial space into the lung lumen ( Fig. 27.1 ) ( ). Sodium ions and water follow passively down electrical and osmotic gradients. A pressure in the lumen of the lung approximately 1 cmH 2 O greater than that in the amniotic cavity is generated, which is essential for lung growth. The presence of lung liquid is important for normal lung development; chronic drainage results in pulmonary hypoplasia ( ), and lung fluid restriction in the embryonic rat lung affects growth but not airway branching ( ). Tracheal ligation increases fetal intrathoracic pressure and causes lung hyperplasia; experimentally this can reverse the pulmonary hypoplasia associated with oligohydramnios and congenital diaphragmatic hernia ( ; ). There is, however, concern that although tracheal ligation results in increased cell proliferation and normal-sized lungs, it may be associated with decreased surfactant production ( ) and altered alveolar structure ( ).
During labour and delivery, the concentration of adrenaline (epinephrine) increases and, as a consequence, lung liquid secretion ceases and resorption begins. Fetal lung liquid absorption is via activation or opening of sodium channels on the apical surface of the pulmonary epithelium ( ). Thyroid hormone and cortisol are necessary for maturation of the normal response of the fetal lung to adrenaline ( ). Exposure to postnatal oxygen tensions increases sodium transport across the pulmonary epithelium ( ).
Amniotic fluid volume
Pulmonary hypoplasia is associated with oligohydramnios following prolonged rupture of the membranes or chronic drainage following amniocentesis. It appears to be due to the increased efflux of lung liquid from the intrapulmonary space and not the result of external compression of the fetal thorax squeezing out lung liquid, as the amniotic fluid pressure under such circumstances is at or below the normal range ( ). Prolonged oligohydramnios is associated with a decrease in lung liquid volume and a reduction in both the rate of lung liquid secretion and tracheal fluid flow rate ( ).
The pulmonary blood vessels and lymphatics develop from the mesenchyme of the splanchnic mesoderm of the foregut; this surrounds the lung buds as they push out from the laryngeal floor. Adjacent blood vessels fuse to form a rudimentary vasculature. The vascular plexus within each lung bud becomes supported by paired segmental arteries, which arise from the dorsal aorta. At 32 days of gestation, the sixth branchial arches appear, which give off the pulmonary arteries, hence the segmental arteries cease to supply the lung. By 50 days of fetal age, the adult blood supply pattern is achieved. Occasionally, an early segmental artery persists, captured within a lobe or lung segment (see sequestered lobe, p. 587 ) ( ). There is progressive dichotomous branching of the pulmonary arteries during lung growth; 70% of the preacinar arteries are formed between the 10th and 14th week of gestation. Additional branching in the canalicular phase and in the last trimester around the developing saccules greatly increases the vascular supply to the area of gas exchange.
During fetal as compared with adult life, the arterial walls contain a greater proportion of smooth muscle. Postnatally, there is rapid thinning – in the first 2 weeks, due to distension, and over the next year, due to a slow reduction in the number of muscle fibres ( ). If such remodelling does not occur, the pulmonary vascular resistance (PVR) remains high, leading to persistent pulmonary hypertension ( p. 495 ). Abnormal remodelling alters the pulmonary vascular reactivity and the response to pharmacological agents. Normal postnatal development can be divided into three overlapping phases ( ; ). Stage 1 starts from birth and lasts for about 4 days, and represents adaptation to extrauterine life. The vessel walls become thinner ( ). Initially, the endothelial cells are squat, have a low surface-to-volume ratio and have many surface projections, but, within 5 minutes after birth, the endothelial cells become thinner with less cell-to-cell contact; fewer projections are evident as their surface membrane material is donated to allow the cells to spread rapidly ( Fig. 27.2 ). During stage 2, when the cells have taken up their definitive position, they deposit connective tissue and fix the wall structure. In stage 3, there is growth of the pulmonary vasculature, which lasts until adulthood. At birth, almost the entire pulmonary vasculature is innervated. The majority of nerves contain the vasoconstrictor neuropeptides tyrosine and tyrosine hydroxylase ( ). Both nerve density and the immunoreactive expression of the neurotransmitters increase particularly rapidly in the first 2 weeks ( ).
Cardiorespiratory adaptation at birth
Aeration of the lungs at birth
In fetal life, the respiratory system is fluid-filled. The replacement of lung liquid by air is largely accomplished within a few minutes of birth. Lung liquid production ceases during labour; that effect is mediated by catecholamines ( ) and arginine vasopressin ( ). Some liquid is squeezed out under the high vaginal pressure during the second stage of delivery ( ), while the majority is absorbed into the pulmonary lymphatics and capillaries ( ). The transpulmonary pressure, which inflates the lungs, displaces liquid from the terminal respiratory units into the perivascular spaces. Air entry into the lung displaces liquid and reduces the hydraulic pressure in the pulmonary circulation, increasing blood flow. This increases the effective vascular surface area for fluid exchange, facilitating water absorption into the pulmonary vascular bed.
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.
Changes in lung mechanics after birth
There is a fall in airways resistance and rise in functional residual capacity (FRC), which is most rapid in the first 2 hours. Compliance, however, progressively increases over the 24-hour period as lung liquid is gradually absorbed. The changes in lung mechanics occur at a slower rate following elective caesarean section, when there is a delay in lung fluid absorption.
Circulatory changes at birth
In the fetus, only about 12% of the right ventricular output enters the pulmonary circulation ( ), because of the high PVR, the presence of a patent ductus arteriosus and the low-resistance placental component of the systemic circulation. At birth, clamping of the umbilical cord and removal of the placenta from the circulation reduce venous return through the inferior vena cava to the right atrium. The foramen ovale closes because of the resultant lower right atrial pressure and the increase in left atrial pressure that occurs with the increased pulmonary venous return. The loss of the umbilical venous return also means diminished flow through the ductus venosus and passive closure occurs usually within 3–7 days of birth.
PVR falls rapidly in the first minutes after birth, then more gradually over the next days and weeks of life. This fall in PVR, which is associated with a structural reorganisation and thinning of the vessel walls, allows for an eightfold increase in pulmonary blood flow. There are several mechanisms responsible for the fall in PVR. Lung aeration results in opening up the pulmonary capillary bed, acute lowering of PVR and an increase in pulmonary blood flow. This is due to both a mechanical effect and oxygenated blood passing through the pulmonary circulation. In fetal lambs, mechanical expansion of the lungs with a non-oxygenated gas caused a decrease in PVR and a fourfold increase in pulmonary blood flow; a further increase resulted when oxygen was used as the ventilatory gas ( ). Inflation of the lungs also stimulates pulmonary stretch receptors, which leads to reflex vasodilation of the pulmonary vascular bed. Mechanical expansion additionally creates surface forces at the gas–liquid interface within the alveoli, which physically expand small blood vessels and decrease perivascular pressure ( ).
Prostaglandins and endothelial-derived products (endothelin-1 and nitric oxide (NO)) are important in regulating fetal and transitional pulmonary vascular tone ( Table 27.2 ) ( ; ). The fetal PVR is high because of the low oxygen tensions and low prostaglandin (PG) I 2 and NO levels and the presence of vasoconstrictor substances such as endothelin-1. In healthy infants, the majority of measurable changes in cardiopulmonary haemodynamics occur by 8 hours, although some degree of right-to-left ductal shunting may be found up to 12 hours after birth ( ). In most infants the ductus has closed or is closing by 24 hours of age, but there is a significant delay in ductal closure in infants with respiratory failure and pulmonary hypertension. During early neonatal life, the pulmonary circulation remains unstable, and in certain disease states, particularly those associated with asphyxia or chronic hypoxia, the PVR increases or remains at the high fetal levels – persistent pulmonary hypertension ( pp. 495–500 ).
|LOWERS PVR||INCREASES PVR|
|Endogenous mediators and mechanisms|
|PGI 2 , E 2 , D 2||Endothelin-1|
|Adenosine, ATP, magnesium||Leukotrienes|
|Atrial natriuretic factor||Platelet-activating factor|
|Alkalosis||Ca 2+ channel activation|
|K + channel activation||α-adrenergic stimulation|
|Vagal nerve stimulation|
|Overinflation or underinflation|
|Excessive muscularisation, vascular remodeling|
|Lung inflation||Altered mechanical properties of smooth muscle|
|Vascular cell structural changes||Pulmonary hypoplasia|
|Interstitial fluid and pressure changes||Alveolar capillary dysplasia|
|Shear stress||Main pulmonary artery distension|
|Ventricular dysfunction, venous hypertension|
The nasal portion of the airway is supported by its larger bony and smaller cartilaginous portions. Nasal resistance to airflow, which constitutes approximately one-third of the total pulmonary resistance, is determined by the physical dimensions in a given individual, which are related to ethnic origin ( ), and the state of the mucous membranes lining the airway. The prime function of the nose is to act as an entry port for respiration, humidifying and warming inspired gas and trapping extraneous particles. Infants are not necessarily obligate nose breathers and full-term infants can establish oral breathing in the presence of nasal occlusion ( ). The pharyngeal portion of the airway is very compliant.
Chemoreceptors in the larynx serve to prevent the entry of foreign material by triggering reflex apnoea. Changes in laryngeal diameter modulate airway resistance and lung volume can be maintained by expiratory adduction of the vocal cords ( ). Laryngeal resistance can be varied by active abduction of the vocal cords during inspiration and by passive as well as active adduction during expiration. Inspiratory abduction and expiratory adduction of the vocal cords occur during FBMs.
The trachea and main bronchi are supported by cartilaginous rings; nevertheless, smooth-muscle contraction can cause narrowing and markedly increase resistance, at least in the adult. In the newborn, the small airways are more compliant than in the adult and expiratory collapse tends to lead to air trapping.
In the newborn, compared with the adult, the thorax is round rather than dorsoventrally flattened and the rib orientation is horizontal rather than caudal, thus the expansion potential of the thorax is limited. The neonatal thoracic cage has relatively soft and flexible bony elements, which makes the chest wall subject to collapse during increased inspiratory efforts and the lungs rather collapsed at rest. To compensate, the infant attempts to elevate lung volume at end expiration by a rapid breathing rate, a short expiratory time, intercostal activity and grunting (expiratory laryngeal adduction). Grunting disappears in rapid eye movement (REM) sleep ( ). Instability of end-expiratory lung volume, particularly in the premature neonate, may explain fluctuations in arterial oxygen levels ( ).
The respiratory muscles ( Fig. 27.3 )
The main inspiratory muscle is the diaphragm, a dome-shaped muscle attached to the ribs. Diaphragmatic contraction results in the abdominal contents moving downwards, increasing the vertical dimension of the thoracic cavity. If the dome’s descent is impeded by abdominal pressure, then the lower ribs are pulled up. This increases the ribcage diameter by virtue of the linkages between ribs provided by the intercostal muscles and by the articulations of the ribs that lead to the ‘pump and bucket handle action’. The configurations of the adult and neonatal diaphragm differ, the latter being relatively flat following birth, the dome shape developing with the physical growth of the thorax and internal organs ( ). There is an exaggerated asymmetrical movement of the newborn diaphragm during respiration. These differences mean the diaphragm is less efficient in the neonate than in the adult. The number of skeletal muscle fibres in the diaphragm is, however, fixed at the time of birth and the subsequent increase in muscle weight is due to hypertrophy. The diaphragm consists of: (1) type I fibres, which are oxidative with a slow twitch and fatigue-resistant; (2) type IIa fibres, which are oxidative–glycolytic with a fast twitch but also fatigue-resistant; and (3) type IIb fibres, which are glycolytic with a fast twitch and are fatigable ( ). The proportion of type I fibres is low at birth and increases until 6 months of age; there is an associated increase in type IIb, but a decrease in type IIa fibres. Type IIc fibres, which are present at birth, disappear completely by 6 months ( ). This means that at birth the diaphragm has a relatively high percentage of oxidative fibres (type I, IIa and IIc) which are fatigue-resistant. The proportion of type I fibres, however, may be low in the preterm infant, putting the baby at risk of diaphragmatic muscle fatigue. Optimal function of the diaphragm is dependent on ribcage stability and adequate abdominal muscle tone. This is particularly important when the system is loaded, as with stiff lungs or obstructed airways.
Upper airway muscles
Patency of the upper airway is dependent on the upper airway muscles and the diaphragm. There is active contraction of the laryngeal muscles, particularly in early expiration, and there is relatively late relaxation of the inspiratory muscles. That activity reduces the flow rate and is modified by carbon dioxide levels; high levels result in a reduced resistance to flow. If the FRC is reduced, the above muscle activity is increased, such that the airway is almost completely occluded in expiration and gas has to be forced out by contraction of the abdominal muscles, producing a grunt.
Gas exchange in the neonatal lung
At rest, oxygen consumption in the newborn (7 ml/min/kg) is approximately twice that of adults. Minute ventilation is proportionally increased and is achieved largely by an increased breathing rate. The rate is increased because there are constraints on increasing tidal volume imposed by the relatively stiff lungs and unstable ribcage. The disadvantage, however, of increasing rate is that this increases the amount of dead-space ventilation, although the proximal airways have a relatively low volume ( ). Overventilation or underperfusion of some lung units contributes to the wasted ventilation. The contribution of ventilation–perfusion mismatch, as estimated from the arterial–alveolar differences for oxygen (a-AD o 2 ), is most marked in preterm infants in the first hours after birth.
A major difference between the blood gases of newborn and older infants is the lower P a o 2 in relation to the inspired oxygen tension. This is largely because of right-to-left shunting of blood either through areas of the lung with very low ventilation–perfusion ratios or, less commonly, through persisting fetal vascular channels (foramen ovale and ductus arteriosus). Estimates of the total shunt in healthy infants are 24% of the cardiac output in the first hour after birth and 10% at 1 week of age. Shunting through fetal vascular channels is important immediately after birth in immature infants or in sick infants with raised PVR. The low P a o 2 due to right-to-left shunting (through cardiac shunts and perfused but non-ventilated lung units) cannot be overcome by administering 100% oxygen, because the blood that is being ventilated soon becomes fully saturated and increasing the oxygen tension adds little further oxygen. On the other hand, carbon dioxide accumulation from partial right-to-left shunting can be compensated for by increased ventilation of functioning lung units. Thus, provided respiratory efforts are maintained, P a co 2 will be normal or even low, despite right-to-left shunting.
Gas transport in the blood ( )
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 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:
CO 2 + H 2 O → H 2 CO 3 → HCO 3 + H +
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:
CO 2 + R 2 + NH 2 → RNHCOO − + H +
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 ( ).
Regulation of breathing
The rhythmic transition from the inspiratory to the expiratory phase of the respiratory cycle is ordered by a centrally generated respiratory rhythm, which consists of three neural phases:
inspiration, corresponding to inspiratory muscle contraction
phase 1 expiration, corresponding to postinspiration or passive expiration, when inspiratory muscles cease to contract progressively
phase 2 expiration, corresponding to active exhalation with expiratory muscle contraction.
The respiratory rhythm (described above) is generated by a loose complex of respiratory neurons, which lie within the ventrolateral region of the brainstem. The respiratory rhythm generator also produces sighs and gasps. A variety of models of the central respiratory rhythm generator have been proposed, but a common assumption is that chemical neurotransmission is required to mediate the synaptic interactions which play a role in generation of transmission and expression of the respiratory rhythm. Respiratory rhythm-generating areas, such as the pre-Boetzinger complex, receive multiple inputs from many areas outside and within the vicinity of the complex ( ). Afferents from the forebrain, hypothalamus, central and peripheral chemoreceptors, muscles, joints and pain receptors are integrated into the ‘centre’. The number of intersynaptic connections reaches a peak towards the end of fetal life. The complex projects to various respiratory-related areas that contain neuromodulators which are in turn modulated by multiple other areas. Most areas contain multiple neuromodulators that are partly released from the same neurons, thus neuromodulation occurs at all levels of integration ( ).
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 ( ).
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 ( ).
Both central and peripheral chemoreceptors are involved in modification of respiratory activity in response to changes in blood gases. The central chemoreceptors are situated near the ventral surface of the medulla and respond to changes in carbon dioxide/pH and oxygen supply. The peripheral chemoreceptors are situated at the bifurcation of the common carotid arteries (carotid bodies) and in the aortic bodies above and below the aortic arch, the former being more important in humans.
In the fetus, the arterial chemoreceptors are active in utero, but have reduced sensitivity. They are virtually silenced when the arterial P o 2 rises at birth ( ). Resetting of the carotid chemoreceptors to hypoxia then occurs. This is probably triggered by the rise in blood oxygen levels. The resetting of the chemoreceptors to hypoxia is essentially complete within 24–48 hours of birth ( ) and may be due to a change in dopamine levels. Dopamine inhibits chemoreceptor discharge in both the newborn and adult. If rat pups are delivered into a hypoxic environment (12%), they maintain both their low sensitivity to hypoxia, with persistence of the immature inhibitory response to hypoxia ( ), and a high dopamine turnover. In the lamb, hyperoxia induced by mechanical ventilation of the fetus for a few days before birth causes premature resetting ( ).
Responses to changes in oxygen tension ( Fig. 27.4 )
Fetuses respond to hypoxia with a suppression of ventilation, which is most marked in growth-retarded fetuses ( ); the hypoxic suppression of ventilation is mediated by the lateral part of the lower pons. In response to hypoxia there are also cardiovascular reflexes; these include bradycardia and redistribution of the circulation to favour the heart, brain and adrenals, which minimise oxygen consumption and conserve oxygen supplies for vital organs. Hyperoxia stimulates continuous fetal breathing.
The newborn’s response to hypoxia in the perinatal period is a biphasic response: a transient increase in minute ventilation followed by a decrease to or below baseline levels. The initial increase in ventilation is probably due to activation of peripheral chemoreceptors, as it is abolished by carotid sinus nerve section. The subsequent reduction in ventilation may result from a fall in P a co 2 following the initial hyperventilation and may be due to a depression of central respiratory neurons ( ). It may also be explained by the suppressant effect of hypoxia in the fetal state persisting into the neonatal period. The biphasic response to hypoxia disappears at 12–14 days and the adult pattern is then seen, that is, stimulation without depression ( Fig. 27.4 ). Very immature infants respond to hypoxia in a similar fashion to fetuses, that is, with apnoea. This inhibition of breathing is at a suprapontine level. More mature preterm infants have an initial increase (but less than in term infants) and then a more dramatic fall in ventilation in response to hypoxia ( ). In non-REM sleep, the decrease in ventilation is the predominating response. The response to hypoxia is also modified by the temperature of the environment in which the infant is nursed; transient hyperventilation on exposure to 12% O 2 is not seen if the infant is in a cold rather than a warm environment ( ).
A hyperoxic gas causes a temporary suppression of breathing; this is attributed to the withdrawal of peripheral chemoreceptor drive. During the first few days, the reduction in ventilation with 100% oxygen is less, consistent with inactivity of the carotid afferents during this resetting period. After a few minutes of hyperoxia, ventilation increases to above control levels. In adults, a similar but less marked hyperventilation has been attributed to hyperoxic cerebral vasoconstriction, which leads to increased brain tissue carbon dioxide. The response to hyperoxia is slower in more immature infants. Prolonged exposure to supplemental oxygen also reduces the response to hyperoxia.
Response to carbon dioxide/acidosis
Fetal breathing can be detected as early as 14 weeks of gestation in the human. The amount of time the fetus spends breathing increases with advancing gestational age. Initially, fetal breathing was thought to depend only on behavioural reflexes, as it was only observed during REM sleep. It is now known that fetal breathing is modified by chemical stimuli; the fetus responds to an increase in P a co 2 with an increase in breathing, both elevated frequency and diaphragmatic activity. It is probably that the hydrogen ion concentration, rather than carbon dioxide per se, is the major stimulus to respiratory activity, although there is some evidence that carbon dioxide may have an effect independent of pH ( ). During non-REM sleep, however, only very high P a co 2 levels (>100 mmHg) can initiate breathing activity ( ). Hypoxia inhibits fetal breathing. Lesions in the ventrolateral pons eliminate the hypoxic inhibition of breathing and are associated with a lower threshold for carbon dioxide drive-augmented breathing through all states ( ). Fetal breathing is also suppressed during labour.
Inhalation of CO 2 increases ventilation in the newborn in both REM and quiet sleep. The slope of minute ventilation versus P a co 2 levels in the newborn is similar to that of adults, but the response is shifted to the left because of lower resting carbon dioxide levels ( ). The tidal volume component of the ventilatory response assumes greater importance with postnatal development. The percentage of inhaled CO 2 influences the pattern of breathing. A low percentage of CO 2 (2%) primarily stimulates an increase in tidal volume ( ), whereas a higher percentage provokes an increase in respiratory frequency and tidal volume ( ). Periodic breathing is abolished with a small increase in inhaled CO 2 ( ). Sleep state also influences the response to carbon dioxide, both in adults ( ) and in the newborn. In term infants, the slope of ventilatory response is less during active than quiet sleep ( Fig. 27.5 ). This may be due to mechanical instability associated with ribcage distortion in active sleep, since the diaphragmatic response is intact. In preterm infants ( ), the slope of the ventilatory response is less, but increases with postnatal growth. As diaphragm electromyogram responses to CO 2 inhalation are also reduced in the preterm infant, this is probably due to the immaturity of the central chemoreceptors rather than mechanical differences in the respiratory pump ( ).
The Hering–Breuer reflexes
described three respiratory reflexes. The Hering–Breuer inflation reflex is stimulated by lung inflation and results in cessation of respiratory activity. This reflex is generated by stretch receptors within the airway and has an afferent pathway lying within the vagi. In the newborn, the reflex produces a pattern of rapid, shallow tidal breathing and operates within the tidal volume range. The reflex is active from FRC and is maximal after an inspiration of approximately 4 ml/kg above FRC ( ).
The Hering–Breuer expiratory reflex is stimulated if inhalation is prolonged. The active expiration seen in infants ventilated at slow rates and long inflation times may be a manifestation of this reflex ( ).
In animal models, the Hering–Breuer deflation reflex is evidenced by a prolonged inspiration generated in response to deflating the lung rapidly, either by attaching the endotracheal tube to a suction source or creating a pneumothorax, or following an unusually vigorous expiratory effort which takes the lung below its end-expiratory level. This response does occur in the newborn ( ) and may have a role in maintaining the FRC. The strength of the reflex is increased if rapid lung volume reduction is commenced at FRC rather than end inspiration ( ).
Head’s paradoxical reflex
noted that, if vagal conduction was blocked, rapid inflation, instead of producing apnoea, resulted in a stronger and more pronounced diaphragmatic contraction; this was named Head’s paradoxical reflex. It has subsequently been termed the inspiratory augmenting reflex or provoked augmented inspiration and is the underlying mechanism of the first breath and sighing. This reflex improves compliance and reopens partially collapsed airways. It has an important role in promoting lung expansion during resuscitation. Its frequency is increased by low compliance, hypercapnia and hypoxia ( ).
The intercostal phrenic inhibitory reflex
Rapid chest wall distortion results in a shortening of inspiratory efforts. This reflex response is inhibited by an increase in FRC or applying continuous positive airway pressure; the mechanism may be improved chest wall stability ( ).
Subepithelial chemoreceptors in the trachea, bronchi and bronchioles detect insults to the epithelial surfaces; thus, inhalation of toxic gases causes a change in frequency and depth of respiration. The response is less in REM sleep and in the premature infant ( ), who has a smaller number of small myelinated vagal fibres and poorly developed receptors.
Upper airway reflexes
Breathing is stimulated by cold via the trigeminal afferents of the facial skin, whereas irritant stimuli to the nasal mucosa cause inhibition of breathing and cardiovascular reflex responses resembling those in diving mammals. The latter response is enhanced under anaesthesia and in the newborn ( ), when cortical dampening of the responses is reduced. Vigorous suctioning of the nasopharynx can stimulate apnoea and bradycardia via these reflexes ( ).
The laryngeal chemoreceptors defend the lower airway from inhalation. Introduction of water into the interarytenoid notch induces apnoea ( ). In active sleep, laryngeal stimulation is more likely to induce apnoea and less likely to cause arousal ( ). This is of potential clinical significance since gastro-oesophageal reflux is more common during active sleep ( ). Maturation of the laryngeal chemoreflex is characterised by an increase in coughing and a decrease in swallowing and apnoea ( ). Those changes are probably the result of central processing of afferent stimuli rather than of a reduction in sensitivity or change in receptor distribution in the larynx ( ).
Lung mechanics ( Table 27.3 )
The tidal volume is the amount of gas entering or leaving the lung with each breath. Minute volume is calculated by multiplying the tidal volume by the respiratory rate over 1 minute. The volume exchanged following a maximum inspiratory and expiratory effort is called the vital capacity and in the infant can be measured during crying (crying vital capacity), or more accurately by pressurising a face mask to 20–25 cmH 2 O and then inflating a rigid walled jacket with pressures of 40–60 cmH 2 O ( ). The residual volume remains after a maximum expiratory effort; residual volume plus vital capacity gives the total lung capacity. At end expiration, the volume of gas remaining in the lung is referred to as the FRC and can be estimated by rebreathing an inert gas, such as helium (FRC he ). Only areas of the lung in communication with the airways will be measured by such a method. Alternatively, the patient can be placed in a body plethysmograph and the FRC pleth estimated by applying Boyle’s law during airway occlusion; FRC pleth is FRC he plus trapped gas. The dead space is the part of the respiratory system which does not take part in ventilation and is made up of the anatomical dead space (the conducting airways) and the physiological dead space, which includes non-functioning alveoli. Alveolar ventilation can be estimated from the tidal volume minus the dead space. In infants with respiratory distress, particularly transient tachypnoea of the newborn, the respiratory rate is increased and the tidal volume may be decreased. In respiratory distress syndrome (RDS) and pneumonia, the FRC is low and the physiological dead space increased.
|Measurements||NO. OF INFANTS STUDIED||MEAN||STANDARD DEVIATION||RANGE|
|Tidal volume (ml/kg)||266||4.8||1.0||2.9–7.9|
|Respiratory rate (breaths/min)||266||50.9||13.1||25–104|
|Minute volume (ml/min/kg)||266||232||3.6||78–444|
|Dynamic compliance (ml/cmH 2 O/kg)||266||1.72||0.5||0.9–3.7|
|Total pulmonary resistance (cmH 2 O/l/s)||266||42.5||1.6||3.1–171|
|Work of breathing (G.cm)||266||11.9||7.4||1.1–52.6|
|Expiratory time (s)||291||0.57||0.17||0.27–1.28|
|Inspiratory time (s)||291||0.51||0.10||0.28–0.87|
|Time to maximum expiratory flow/total expiratory time (s)||291||0.51||0.12||0.18–0.83|
|Static compliance (ml/cmH 2 O/kg)||299||3.70||1.45||2.0–14.8|
|Respiratory system resistance (cmH 2 O/l/s)||299||63.4||16.6||34.9–153.3|
|Time constant of respiratory system (s)||299||0.24||0.10||0.08–1.1|
|Thoracic gas volume (ml/kg)||271||29.8||6.2||14.5–45.6|
Compliance is a measure of the distensibility of the lungs and chest wall, the change in volume per unit pressure. Dynamic compliance is assessed during tidal breathing by measurement of the change in volume (usually using the integrated signal of a flow-measuring device, a pneumotachograph) divided by the change in pleural pressure (which under certain conditions is similar to the change in oesophageal pressure) between points of zero airflow ( Fig. 27.6 ). In situations with a rapid respiratory rate and chest wall distortion, dynamic compliance measurements can be inaccurate. Dynamic compliance is measured in ventilated infants by relating the volume change from a positive pressure inflation to the pressure drop (that is, positive inflation pressure – positive end-expiratory pressure), providing that the infant is not making spontaneous respiratory efforts, as these might interfere with volume delivery during inflation.
Static compliance requires the measurement of changes in lung volume over a larger range than the tidal volume or an assumption has to be made that the end-expiratory transpulmonary pressure represents a static value, which is unlikely to be true in infants with lung disease ( ). Static compliance is usually measured in spontaneously breathing infants using an occlusion technique, which relies on occlusion at end inspiration causing a transient inhibition of breathing by stimulation of the Hering–Breuer reflex. The airway pressure during the occlusion is related to the volume above end expiration at which the occlusion was made. This technique requires temporary cessation of breathing, which may be difficult to provoke in an infant with a rapid respiratory rate or a weak Hering–Breuer reflex. Static compliance measurements assess the compliance of both the lung and chest wall. In the newborn, the chest wall compliance is very high, so, essentially, dynamic and static compliance values are similar. Compliance is reduced in infants with RDS.
Resistance is a measure of the pressure necessary to generate airflow. Airway resistance can be assessed in a body plethysmograph, but after the first week the infant will usually require sedation and this technique is not applicable to oxygen-dependent patients. Pulmonary resistance ( Fig. 27.7 ), however, can be measured on the neonatal intensive care unit, using an oesophageal balloon and pneumotachograph; the pressure difference corresponding to the flow change between points of equal lung volume is measured. Resistance is increased in infants with meconium aspiration syndrome and, at follow-up, in those who required neonatal ventilation ( ). Resistance can also be calculated from the volume and flow traces obtained after the release of the occlusion discussed above. The time constant, the time for 63% of the volume to leave the lungs, can be measured; thus, the resistance can be calculated, as the time constant equals the product of the compliance and the resistance ( ).
Origins of surfactant
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 ( ).
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.
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.
Surfactant is a complex mixture of substances including phospholipids, neutral lipids and proteins.
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.
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 ).
Four surfactant-associated proteins – SP-A, SP-B, SP-C and SP-D – have been identified and constitute 5–10% of surfactant by weight ( ).
Surfactant protein A
SP-A is composed of approximately 248 amino acids ( ). It is a large glycoprotein belonging to the calcium-dependent collectin family of proteins. It constitutes approximately 5% of surfactant by weight. There is considerable heterogeneity in its structure because of extensive posttranslational modification. The human gene is located on chromosome 10; gene expression occurs exclusively in type II pneumocytes ( ), which appear to be the main site of synthesis ( ). Lamellar bodies are enriched with SP-A compared with lung homogenates ( ).
Synthesis of SP-A increases after 28 weeks of gestation ( ). SP-A binds to and confers calcium-dependent aggregation on surfactant phospholipids ( ). SP-A has an essential role in determining the structure of tubular myelin, and the stability and rapidity of spreading and recycling of phospholipids ( ). It regulates the synthesis and secretion of phospholipids, and enhances their uptake by type II cells by binding to specific high-affinity receptors on the apical surface of the type II cells. SP-A partially inhibits surfactant secretion from type II cells ( ) and may prevent the accumulation of surfactant on the alveolar surface. SP-A genetic variants have been reported to predispose to or protect from the development of RDS ( ). SP-A polymorphisms have been associated with severe RSV infection ( ) and an increased risk of bronchopulmonary dysplasia ( ).
Surfactant protein B
The active 79-amino-acid SP-B peptide (molecular weight (MW) 7500–9000) is produced by the proteolytic cleavage of pro-SP-B, a 25 000–33 000 MW precursor protein ( ). SP-B constitutes 1–2% of surfactant by weight ( ). The active SP-B peptide contains highly positively charged amino acids that form an amphipathic helix with the hydrophilic amino acid residues positioned near the phospholipid head groups at the membrane surface. It is composed of two identical polypeptide chains, held together by a disulphide bond ( ). SP-B is encoded by a single-copy gene located on chromosome 2 ( ). The mRNA for SP-B is detectable in human fetal lung tissue as early as 12–14 weeks of gestation, localised in the epithelial cells of bronchi and bronchioles. After 25 weeks it is localised in the type II cells. Glucocorticoids increase expression of SP-B in fetal lung. Expression is restricted to type II pneumocytes and Clara cells. The active SP-B peptide is stored in lamellar bodies and secreted with phospholipids into the airway lumen.
SP-B is required for the formation of tubular myelin and increases the spreading of surfactant phospholipids on to an air–water interface ( ). SP-B disrupts phospholipid vesicles and alters the ordering and packing of the PC molecules. SP-B combined with lipid mixtures constitutes most of the surface activity of natural surfactant in vitro and increases lung compliance in vivo; SP-C and SP-B together are even more effective. SP-C and SP-B both stimulate lipid uptake in isolated cells. SP-B can also protect the pulmonary surfactant film from inactivation by serum proteins ( ).
Absence of SP-B influences the composition of pulmonary surfactants. It is associated with absence of or markedly decreased PG and an additional aberrant SP-C peptide ( ). DPPC synthesis is preserved in SP-B deficiency but SP-C cannot be processed to its active peptide and no secretion of normal surfactant occurs ( ). In SP-B knockout mice, both lamellar bodies and tubular myelin structures are absent. SP-B deficiency, with complete absence of SP-B, is an autosomal recessively inherited disorder ( ). SP-B deficiency causes hypoxaemic respiratory failure and leads to lethal respiratory failure within the first year of life and is refractory to mechanical ventilation, surfactant therapy, glucocorticoids and extracorporeal membrane oxygenation ( ; ). It can present as a congenital form of alveolar proteinosis, but not all cases have this feature; pulmonary hypertension is a prominent clinical finding. Lung transplantation is currently the only successful intervention. More than 27 loss-of-function mutations have been identified in the SP-B gene, resulting in lethal neonatal failure. The most frequent mutation is a 121ins2 frameshift mutation, accounting for 60–70% of cases ( ). The gene frequency of this mutation is 1 per 1000–3000 ( ) and the condition is rare – an extimated disease incidence of 1 in 1.5 million births ( ). Partial deficiencies of SP-B with less severe clinical courses have now been reported ( ).
Surfactant protein C
This small hydrophobic protein has a MW of 3000–6000 depending on the separation system used. It constitutes 1–2% of surfactant by weight and is unique to surfactant. The mRNA for SP-C is present from early lung morphogenesis at the distal tips of the branching airways ( ), but subsequently SP-C expression occurs only in the type II cells. The SP-C gene is located on chromosome 8 ( ). SP-C contains 35 amino acids and is likely to be a transmembranous peptide. It has a hydrophobic valine-rich region, which may be required for its function. SP-C can impart surface-like properties to phospholipids ( ). Concentrations as low as 1% can dramatically enhance surface adsorption and spreading of phospholipids in vitro. It may play a role in enhancing the reuptake of phospholipids. Surprisingly, SP-C knockout mice have normal respiratory function and lung development ( ); it is possible that SP-B replaces SP-C. In humans, however, SP-C deficiency has been associated with an interstitial lung disease ( ; ), and, in a Finnish population, SP-C polymorphisms were associated with RDS and premature birth ( ).
Surfactant protein D
SP-D has a MW of 46 000 and is produced by type II and bronchiolar epithelial cells. Its expression increases with advancing gestation in association with differentiation of terminal airway cells ( ); SP-D production begins in the bronchiolar and terminal epithelium from about 21 weeks of gestation ( ). SP-D expression is widely distributed in epithelial cells in the body; in the lung, SP-D expression occurs in the type II cells, Clara cells and other airway cells and glands. Glucocorticoids increase SP-D expression. SP-D does not have significant surfactant-like activities when mixed with phospholipids. It is, however, involved in the immune function of the lung ( ). SP-D polymorphisms have not been associated with RDS ( ). Indeed, an association has been found between one variant of the SP-D gene and a lower prevalence RDS; the polymorphism was associated with a lower number of repetitive surfactant doses and a lower requirement for supplementary oxygen on day 28 ( ).
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 ( ).
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 ).
Factors affecting surfactant maturation
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 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.
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 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 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 ( ).
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 ( ).
Surfactant physical properties and functions
Surfactant prevents atelectasis and thus reduces the work of breathing. This is achieved by reduction of surface tension and by surfactant becoming a ‘solid’ monolayer, promoting stability of the alveoli, in expiration. Surfactant also prevents the transudation of fluid: in conditions of high surface tension, fluid is sucked into the alveolar spaces from the capillaries.
The presence of an insoluble surface film capable of maintaining a very low surface tension (or high surface pressure) in the air spaces was first inferred by . A small bubble will normally diminish in size and disappear; the smaller it becomes, the more rapidly its diameter decreases. This follows from the relationship described by the Laplace equation:
P = 2 γ / r
where P = internal pressure, γ = surface tension and r = radius, that is, the pressure difference across the bubble’s wall is given by twice the tension in the wall divided by the radius. Thus, in the presence of a high surface tension and small radius, the high pressure difference causes gas to diffuse from the bubble into the surrounding liquid. In the lung, however, the presence of an insoluble surface film means that the surface tension is reduced as the radius decreases.
The contribution of surface tension to the pressure volume behaviour of the lung was demonstrated by , who showed that lungs inflated with saline have a higher compliance than if filled with air. Saline abolishes the surface tension forces, which are an important component of the static recoil force of the lung.
Surfactant lowers surface tension by forming an insoluble surface film. This opposes the surface tension of the underlying liquid by exerting surface pressure. The surface properties of surfactant result from its composition, that is, molecules with both a hydrophobic and hydrophilic chain. When forming a film on water, the polar group is attracted to the water, whereas the non-polar group is turned towards the gas phase. DPPC is a symmetrical molecule and the two straight hydrophobic fatty acid chains allow close packing of the monolayer. Compression of such a monolayer results in it being changed from a liquid to a condensed gel or solid state ( ; ); this is because the transition temperature of the refined mixture rises to above 37°C, so that in vivo the refined monolayer may be solid ( ). In RDS, the PC is relatively unsaturated and of lower quantity than in the mature species. This means an unstable monolayer is formed on compression in expiration, which buckles and does not reduce surface tension effectively. Even when the monolayer has been refined, there is so little DPPC available the alveoli are of small size. Thus, infants with RDS have a low FRC and an increased work of breathing.
Inhibition of surface activity of surfactant by proteins
The alveolar surfactant system may be altered by an inhibitory effect of proteins leaked from the intravascular or interstitial space, owing to an increased permeability of the capillary endothelial and/or alveolar–epithelial barrier ( ). In RDS, the alveolar capillary membrane permeability is increased, and the hyaline membranes are a massive aggregation of fibrin. In addition, proteinaceous material may be inhaled, for example as in meconium aspiration syndrome. There is a marked rank order of potency of proteins in interfering with surfactant function – fibrin monomer > fibrinogen > albumin > elastin > IgG > IgM – such that fibrin has 50 times greater effectiveness than albumin. Once the proteins are present in the surface monolayer, they inhibit the ability of the compressed surfactant to lower surface tension. The leakage of protein on to the alveolar surface, at least in premature rabbits, can be inhibited by surfactant treatment and treatment with antenatal steroids or thryotrophin-releasing hormone. In other conditions, such as meconium aspiration syndrome, the inhibitory effect of the proteins can be overcome by increasing the dose of surfactant. Exogenous surfactants differ with regard to their inhibition by proteins; calf lung surfactant extract and Alveofact are only moderately inhibited by fibrinogen ( ). KL 4 surfactant, which has a synthetic peptide in lieu of SP-B, resists inhibition to serum proteins more than a natural surfactant (beractant) ( ).
Assessment of surfactant maturity
The fluid which is secreted by the fetal lung moves out into the amniotic fluid, carrying surfactant with it. As the lung matures, so the composition of the surfactant in the amniotic fluid changes. The proportion of surfactant (lecithin) in the amniotic fluid can be compared with that of sphingomyelin (L : S ratio). An L : S ratio greater than 2.0 is usually associated with lung maturity and in 95% of cases will predict the absence of RDS. A mature L : S ratio, however, can be associated with RDS in the infants of diabetic mothers or in those with rhesus disease; in these cases, the abnormality is deficiency of PG rather than a lack of DPPC. Relating the amniotic fluid surfactant to the albumin level provides a more reliable predictor of the absence of RDS in infants of diabetic mothers than assessing the amount of DPPC ( ). Unfortunately, an L : S ratio <2.0 predicts RDS with an accuracy of only 54%. The lower the L : S ratio, the more likely the baby is to develop RDS: 21% of babies with an L : S ratio of 1.5–2.0 are affected, compared with 80% with an L : S ratio below 1.5.
Identification of PG in the amniotic fluid is helpful, as babies with PG rarely develop RDS. A combination of a low L : S ratio with absence of PG from amniotic fluid samples obtained within 3 days of delivery is a better predictor of the duration of respiratory support than is either gestational age or birthweight, but only in pregnancies not complicated by premature rupture of the membranes ( ). In diabetic pregnancies, the presence of PG correlated to an L : S ratio of >3.0 and a lamellar body count of at least 50 000 ( ).
The L : S ratio can also be assessed in fluid from the pharynx ( ; ; ) or stomach ( ). This can give retrospective demonstration that a baby had mature lungs at birth or provide further documentation on the course of a baby’s illness ( ).
The level of serum SP-A in the first 24 hours has been shown to increase with advancing gestational age and differs significantly between infants with and without RDS ( ). SP-A can also be measured in cord blood using an enzyme-linked immunosorbent assay system, so has been suggested to be a useful serum marker to predict the development of RDS ( ). Tests of surfactant maturity, however, are now rarely employed, as many clinicians have the policy of giving exogenous surfactant very soon after birth to all infants born below a certain gestational age, because of the proven efficacy of prophylactic surfactant administration. Such tests may, however, be useful in developing countries ( ).
Acute respiratory disease
Respiratory distress syndrome
Respiratory distress syndrome (RDS), in non-intubated babies who have not received exogenous surfactant therapy or been exposed to antenatal corticosteroids, is characterised by a respiratory rate >60/min, dyspnoea (intercostal, subcostal indrawing, sternal retraction) with a predominantly diaphragmatic breathing pattern and characteristic expiratory grunt, all presenting within 4–6 hours of delivery. Oxygen administration is required to prevent cyanosis and there is a reticulogranular chest X-ray (CXR) appearance as a result of widespread atelectasis. Nowadays, that presentation is very unusual; antenatal corticosteroids are routinely given and very prematurely born babies are intubated and given surfactant usually within the first hour after birth. The diagnosis in such babies then is based on their premature birth and CXR appearance. Pathophysiologically, the condition is characterised by non-compliant (stiff) lungs, which contain less surfactant than normal and become atelectatic at end-expiration. Histologically, hyaline membranes line the terminal airways. These membranes give the condition its alternative name, hyaline membrane disease (HMD), which, to be semantically correct, should be used only in the presence of histological confirmation; thus, the term RDS is preferred.
In the modern era of neonatal intensive care, approximately 1% of infants develop RDS ( ).
RDS results from immaturity of the lungs, particularly the surfactant-synthesising systems. Various factors contribute to the immaturity and others interact with it to increase or decrease the incidence of the disorder.
The risk of RDS is inversely proportional to gestational age: 50% of babies less than 30 weeks of gestational age, as compared with 2% of those between 35 and 36 weeks, develop RDS ( ). RDS is almost invariable in infants of less than 28 weeks of gestation, but it does remain a significant problem up to 34 weeks’ gestation ( ). The maturation of surfactant synthesis is a mirror image of the incidence of RDS at different gestations. Some of the dyspnoea and hypoxaemia in very preterm babies is due to their immature lung structure, with increased connective tissue and poorly developed alveoli. Other factors make the preterm neonate inherently susceptible to RDS. Their lung epithelia are more leaky than those of a baby born at term, increasing the likelihood of protein passing on to the alveolar surface, where it will inhibit surfactant function (see below). They are more prone to asphyxia, hypoxia, hypotension and hypothermia, all of which are likely to impair surfactant synthesis or increase alveolar capillary leakiness.
Boys are much more likely to develop RDS than girls, with a male-to-female ratio of 1.7 : 1, and are more likely to die from the disease ( ). In male fetuses, the delayed maturation of the lecithin-to-sphingomyelin (L : S) ratio and late appearance of phosphatidylglycerol (PG) ( ) are androgen-induced ( ; ).
Black babies have a lower incidence of RDS – 60–70% of that of white babies of the same gestational age ( ). This is evident even in very immature babies: in one series only 40% of African infants <32 weeks’ gestational age developed RDS, compared with 75% of Caucasian infants ( ). No black baby with an L : S ratio >1.2 developed RDS, but white babies did develop the disease at those low ratios ( ). Allelic variation in the surfactant protein A gene has been reported between American whites and Nigerian blacks ( ).
Caesarean section carried out before the mother went into labour was reported to increase the risk of her baby developing RDS ( ; ), although this was not a consistent finding. Data from infants born at gestations above 32–34 weeks confirm the association of caesarean section before labour with both RDS and transient tachypnoea of the newborn (TTN) ( ; ). The timing of the caesarean section is also important: the need for mechanical ventilation is 120 times greater after elective caesarean section at 37–38 weeks as compared with 39–41 weeks in babies with surfactant deficiency ( ). Review of 24 077 repeat caesarean deliveries at term demonstrated that births at 37 and 38 weeks compared with 39 weeks were associated with an increased risk of a composite outcome of neonatal death, respiratory complications, hypoglycaemia, newborn sepsis and admission to the neonal unit ( ). A review of nine studies comparing the outcome by mode of delivery of at or near-term infants demonstrated that all studies reported elective caesarean section was associated with an excess of respiratory morbidities with an average increased risk of two- to threefold ( ).
Babies who are depressed at birth are at increased risk of RDS. The incidence of RDS in babies less than 32 weeks of gestation was 54% in those with an Apgar <4 compared with 42% in babies with Apgars >4 ( p < 0.005) ( ). During fetal asphyxia, lung perfusion falls, resulting in ischaemic damage to pulmonary capillaries. When the fetus recovers from the acute asphyxia, pulmonary hyperperfusion occurs and, if delivery occurs shortly afterwards, a protein-rich fluid leaks out of the damaged pulmonary capillaries. This leakage of proteins inhibits surfactant activity on the alveolar surface ( ). The protein leak can be prevented by exogenous surfactant ( ), but in babies who respond poorly to surfactant administration, this benefit is probably overwhelmed by a large alveolar protein leak ( ). The surfactant protein (SP)-A ( p. 460 ) is of specific benefit in minimising the inhibitory effect of protein on either endogenous or exogenous surfactant ( ). One of the beneficial effects of antenatal steroids ( p. 462 ) is that they reduce this capillary leakiness ( ). The association between asphyxia and RDS is also influenced by hypoxia and acidaemia, predisposing to pulmonary hypertension and hypoperfusion with a right-to-left shunt ( p. 498 ) and reducing surfactant synthesis by inhibiting the synthetic enzymes. RDS following birth depression blends into a spectrum with acute RDS (ARDS).
Fetuses of diabetic mothers have abnormal surfactant synthesis, in particular a delay in the appearance of PG ( ). Insulin delays the maturation of alveolar type II cells and decreases the proportion of saturated phosphatidylcholine in the surfactant ( ). There are decreased levels of SP-A in amniotic fluid from diabetic pregnancies as compared with fluid from non-diabetic women ( ). In cultured human lung tissue, insulin inhibits accumulation of SP-A and its mRNA ( ; ). The incidence of RDS in infants of diabetic mothers (IDM) is increased by elective caesarean section before labour at 36–37 weeks. Improvements in maternal diabetic control during pregnancy have now facilitated delay in delivery until the 39th–40th week of gestation and RDS now occurs in fewer than 1% of patients ( ), even though in some the surfactant pattern at amniocentesis remains immature ( ).
Thyroid activity is important in the prenatal development of the surfactant system ( p. 459 ). Preterm babies who develop RDS have lower levels of thyroid hormones in their cord blood than controls ( ; ). The postnatal nadir in serum thyroxine concentration (seen in preterm infants) is very low in neonates with RDS ( ). Most term babies with congenital hypothyroidism detected by screening do not develop RDS, but some cases do occur ( ).
There are reports of families in which several relatively mature babies have developed RDS. At preterm gestations, if a woman has one baby with RDS, the relative risk of RDS in a subsequent low-birthweight (LBW) baby may be increased threefold ( ). SP-B deficiency results in lethal respiratory failure ( ), which is associated with histopathological features of congenital alveolar proteinosis ( ). This abnormality has been described in families ( ) and the inheritance is autosomal recessive. Partial deficiency of SP-B, which may be compatible with survival, has been reported ( ). Polymorphisms in intron 4 of the SP-B gene have been found to modify the course of RDS independently, as indicated by the frequency of severe RDS and the occurrence of bronchopulmonary dysplasia (BPD) ( ). Specific alleles of the SP-A and SP-B genes associate interactively with susceptibility to RDS and dominant mutations of SP-C associate with BPD ( ).
The second twin is more likely to develop RDS ( ), although this is not a consistent finding and others have reported no difference between twins and singletons ( ). There is similarity of L : S ratios in twins, which is greater in monozygotic than dizygotic pairs ( ).
Surfactant function is defective in cold babies and the concomitant hypoxia and acidaemia impair surfactant synthesis ( ). In addition, below 34°C, even in the presence of adequate amounts of PG, dipalmitoyl phosphatidycholine (DPPC) cannot spread to form an adequately functioning monolayer. Hypothermia in animals induces pulmonary hypertension and a fall in P a o 2 ( ); similar mechanisms may occur in neonates. Coagulation disorders are more common in hypothermic infants.
In animal studies, maternal malnutrition compromises fetal surfactant synthesis as well as lung growth ( ). Postnatally, although calorie deprivation does not appear to be important ( ), specific deficiencies of fatty acids or inositol may be relevant ( ). Inositol supplementation in babies with RDS improves outcome ( ), reducing the risk of BPD or death, and severe retinopathy of prematurity (ROP) ( ).
Intrauterine growth retardation
An appropriately grown infant of 28 weeks’ gestational age is much more likely to develop severe RDS than a growth-retarded 32-week-gestation infant of similar birthweight ( ). Severely growth-retarded infants, however, have a higher incidence of RDS and it is more severe ( ; ).
Haemolytic disease of the newborn
The development of pulmonary maturity may be delayed in severely affected infants with haemolytic disease of the newborn with or without hydrops ( ). A possible mechanism is the increased levels of insulin due to beta-islet cell hypertrophy, as occurs in IDM ( Ch. 22 ). The presence of heart failure with proteinaceous pulmonary oedema fluid aggravates any pre-existing surfactant deficiency due to prematurity.
Time of cord clamping
Preterm neonates who had undergone early cord clamping and had a low red cell mass, particularly when combined with some degree of birth depression, were more prone to develop RDS. As a consequence, it was recommended that following preterm delivery the cord should not be clamped until 1–2 minutes after delivery ( ). A small prospective study of babies less than 33 weeks’ gestation showed that a 30-second delay in cord clamping had no effect on mortality, but that the late-clamped babies were easier to ventilate in the first few days and required fewer blood transfusions ( ).
Factors with equivocal effects on the incidence of RDS
Some have reported a higher incidence of RDS in preterm infants of hypertensive mothers ( ), perhaps due to delivery by caesarean section before labour. In contrast, no effect of pre-eclampsia with or without growth retardation was demonstrated on the results of lung maturity tests, neonatal morbidity including RDS or mortality ( ; ). In another study, RDS occurred in 15% of infants of mothers with hypertensive pre-eclampsia but in 38% of non-hypertensive controls of similar weight and gestation ( ).
Prolonged rupture of membranes
There is no consensus regarding the impact of prolonged rupture of membranes ( ; ). An apparent benefit may be explained by greater use of antenatal steroids in affected pregnancies ( ).
Factors reducing the incidence of RDS (see prevention of RDS, pp. 473–475 )
Maternal narcotic addiction and smoking ( ) reduce the incidence of RDS. Heroin can mature the surfactant-synthesising systems. The effect of cocaine is unclear ( ; ), although in animal models it induces surfactant synthesis ( ).
The initial histological finding ( ) in non-surfactant-treated infants with RDS is alveolar epithelial cell necrosis developing within half an hour of birth. The epithelial cells become detached from the basement membrane and small patches of hyaline membranes form on the denuded areas. At the same time, there is diffuse interstitial oedema. The lymphatics are dilated by the delayed clearance of fetal lung fluid and the capillaries next to the membranes have a sludged appearance. There are very few osmiophilic granules in the type II cells, which in places contain vacuoles, suggesting that all the lamellar bodies have been discharged. In the early stages, all these changes are rather patchy, but, by 24 hours, more extensive generalised membrane formation in the transitional ducts and respiratory bronchioles occurs. Hyaline membranes line the overdistended terminal and respiratory bronchioles ( Fig. 27.11 ), particularly where the airways branch, and may extend into the putative alveolar ducts. The most distal component of the respiratory unit, the terminal sacs, although collapsed, are not lined by membranes. The hyaline membranes are eosinophilic on staining with haematoxylin and eosin, and contain nuclear debris from necrotic pneumocytes. Occasionally, when the infant has hyperbilirubinaemia, the membranes are yellow, reflecting the presence of unconjugated bilirubin. The hyaline membranes are formed by coagulation of plasma proteins, which have leaked on to the lung surface through damaged capillaries and epithelial cells; the fibrillary component of the membranes is derived from exuded fibrin. After 24 hours, a few inflammatory cells appear within the airway lumen; macrophages are usually the most prominent cell, although some polymorphs may also be present. Ingestion of the membrane by macrophages takes place over the next 2 or 3 days as the membrane separates. Macrophages are also present beneath the membrane within the interstitium, which is usually oedematous and where there may be a mild fibroblastic response. Epithelial regeneration is detectable after 48 hours, usually beneath the separating membranes. Cuboidal cells from the unaffected transitional ducts become large and mitotic; they flatten out and spread beneath the hyaline membranes. Other cells produce lamellar bodies. Many of these reparative cells form abnormally thick epithelial squames and, with damaged capillaries, can present a considerable barrier to efficient gas exchange. During this stage of repair, surfactant can be detected in increasing quantities on the alveolar surface ( ). By 7 days of age, the hyaline membranes will have disappeared in an infant with uncomplicated RDS. In ventilated babies, however, the healing process is markedly altered and delayed. There is a hyperplastic healing process, with massive shedding of bronchiolar epithelial cells and type II pneumocytes. Hyaline membranes remain prominent. The terminal airways may be plugged with secretions and there is progressive scarring and fibrosis of the alveoli and airways, leading to the picture of BPD ( p. 552 ).
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 ( ; ).
|Tidal volume ( V T )||4–6 ml/kg|
|Minute volume ( V E )||250–400 ml/kg/min|
|Alveolar ventilation ( V A )||50–90 ml/kg/min|
|Physiological dead space ( V D / V T )||60–75%|
|Functional residual capacity (FRC)||3–20 ml/kg|
|Crying vital capacity||20–30 ml|
|Dynamic compliance ( C L )||0.0003–0.0005 l/cmH 2 O/kg|
|Inspiratory resistance ( R aw Insp )||55–95 cmH 2 O/l/s|
|Expiratory resistance ( R aw Exp )||140–200 cmH 2 O/l/s|
|Work of breathing||800–3000 g.cm/min/kg|
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:
0.001 l / cmH 2 O ( compliance ) × 100 cmH 2 O / l / s ( resistance ) = 0.1 seconds ( time constant )
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 ( ).
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 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:
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.
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 ( ; ).
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 ( ; ; ).
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 respiratory distress syndrome
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.
|Improved Apgar scores|
|Maturation of lung structure|
|Initiation of surfactant protein synthesis|
|Improved NO-mediated pulmonary venous relaxation|
|Reduced pulmonary capillary leakiness|
|Interaction with postnatal exogenous surfactant therapy||p. 475|
|Increased resistance to high oxygen exposure|
|Better blood pressure in early neonatal period|
|Higher neonatal white cell counts|
|Less patent ductus arteriosus||;|
Timing of treatment
Results from randomised trials have demonstrated that the benefit is maximal in babies delivered between 24 and 168 hours after starting the maternal therapy ( ). A smaller but useful benefit is also seen in women receiving less than 24 hours of therapy.
Number of courses
There are doubts about the safety of multiple courses of corticosteroids ( ; ), which cannot be recommended as routine treatment. Repeated courses of therapy may suppress the maternal and fetal hypothalamic–pituitary–adrenal axis ( ), as well as increasing the risk of maternal hyperglycaemia and infection. Neonatal Cushing syndrome as been reported after repeated antenatal courses of steroids ( ). Steroids, however, may depress the neonatal adrenal gland when used in conventional doses ( ). Evidence from eight randomised controlled trials in animal models highlighted that, although repeated doses of antenatal corticosteroids have beneficial effects in terms of lung function, they can have adverse effects on brain function and fetal growth ( ). Similar effects have been seen in infants following repeated courses. In one study ( ), infants exposed to more than four courses had significant weight reductions. In a large randomised study ( ), although repeated courses of steroids (weekly) reduced both the risk of RDS and need for supplementary oxygen and shortened the duration of mechanical ventilation, z scores for weight and head circumference were lower at hospital discharge. In another large randomised study ( ), infants exposed to repeated courses (fortnightly) had similar morbidity and mortality, but weighed less, were shorter and had a smaller head circumference ( ). Data regarding the efficacy of rescue steroids after only one standard administration are mixed. A single rescue course of antenatal corticosteroids before 33 weeks in women who had completed a single course before 30 weeks of gestation was associated with a lower rate of neonatal morbidity and significantly decreased RDS and surfactant use ( ), but in another study the requirement for surfactant was increased in infants exposed to a single repeated dose of betamethasone ( ). A single repeated dose of antenatal betamethasone given for imminent preterm birth at least 1 week after standard betamethasone treatment, however, was not shown to influence neurodevelopmental outcome and had no signifcant effect on growth at 2 years of age ( ).
In the original study by , the greatest benefit was seen at gestations of 30–34 weeks, with a much smaller, although statistically significant, benefit below 30 weeks. Crowley’s meta-analysis ( ) demonstrated a benefit in neonates less than 31 weeks, but evidence for benefit in babies of less than 28 weeks is less strong ( ; ).
Preterm rupture of membranes
Although there has been concern that, in PROM, antenatal steroids may increase risk of infection, with appropriate clinical surveillance this was not a problem in the studies reviewed by ; indeed, a beneficial effect of antenatal steroids in pregnancies complicated by PROM was demonstrated.
reported that steroid-treated hypertensive women had a significantly increased stillbirth rate and perinatal mortality; as a consequence, such women were excluded from trials ( ). Clinical experience and observational studies, however, suggest that steroids can be used safely in this situation ( ).
In the past, glucocorticoids were avoided in diabetic pregnancies because of their potential for causing hyperglycaemia; however, they should be given, as the insulin regimen can be altered during the brief period of hyperglycaemia. Steroids switch on the surfactant protein-synthesising systems in experimental diabetic rats ( ).
Multiple pregnancies have often been excluded from trials of antenatal corticosteroids.
Guidelines for antenatal steroid usage
Guidelines have been produced by the , the British Association of Perinatal Medicine ( ), and the National Institutes of Health of the USA ( ). Their recommendations include:
Antenatal treatment with corticosteroids should be considered for all women at risk of preterm labour between 24 and 36 weeks. Treatment should consist of two doses of betamethasone given intramuscularly 24 hours apart or four doses of dexamethasone given 12 hours apart. Betamethasone, however, is now preferred, as in an observational study ( ) it was associated with a lower risk of periventricular leukomalacia (PVL). In a non-randomised comparison, betamethasone compared with dexamethasone was associated with lower rates of RDS and BPD ( ).
Treatment for less than 24 hours is associated with significant improvement in outcome; thus, corticosteroids should be given unless immediate delivery is anticipated.
In the absence of chorioamnionitis, antenatal corticosteroids are recommended in pregnancies complicated by preterm PROM.
Unless there is evidence that corticosteroids will have an adverse effect on the mother, they are also recommended in other complicated pregnancies.
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 ( ).
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 ( ).
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 ( ).
|TYPE OF SURFACTANT||ANIMAL SOURCE||COMPOSITION (OR ADDITIVES IF ANIMAL-DERIVED)|
|Protein-containing animal surfactants|
|Surfactant TA||Cow||DPPC, palmitic acid triglyceride|
|Survanta||Cow||Similar to Surfactant TA|
|Alveofact SF-RI 1||Cow|
|Human surfactant||Liquor amnii|
|ALEC (Pumactant)||70% DPPC, 30% PG|
|Exosurf||DPPC + tyloxapol and hexadecanol|
|Peptide-containing synthetic surfactants|
|Venticute||DPPC, POPG, PA, rSP-C|
|Lucinactant||Synthetic SP-B analogue made of lysine–leucine (KL4)|
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.
Clinical features of respiratory distress syndrome
The diagnostic criteria for RDS were laid down before use of prophylactic surfactant. These comprised: a respiratory rate above 60/min; grunting expiration; indrawing of the sternum, intercostal spaces and lower ribs during inspiration; and cyanosis without added oxygen ( ).
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 ( ).
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.
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.
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 ).
Differential diagnosis ( Table 27.7 )
The differential diagnosis in the first 6 hours can usually be made on the basis of the history (including the gestation), the clinical examination, the blood gases and the CXR. It is impossible, however, to exclude infection as the cause of the baby’s symptoms. Furthermore, infection with group B streptococcus (GBS; Streptococcus agalactiae ) can coexist with RDS. As a consequence, it is important to treat all infants presenting with respiratory distress with antibiotics until the results of cultures are available. PPHN ( p. 495 ) can be differentiated by the absence of significant parenchymal lung disease and the relevant echocardiographic findings. Infants with RDS, however, may also have marked pulmonary hypertension ( ). Such infants will have an oxygen requirement that is out of proportion to their CXR appearance and a poor response to surfactant therapy. Respiratory distress presenting after 4–6 hours of age in an infant who has been adequately observed is usually due to pneumonia or heart failure secondary to heart disease. Other conditions, such as aspiration and inhalation of the feed, some malformations and, occasionally, a small pneumothorax can present after 6 hours of age, but these are less common.
|CONDITION||GESTATIONAL AGE||HISTORY||EXAMINATION *||GASES †||PRESENTATION ‡||CHEST RADIOGRAPH||COMMENTS|
|<6 h||>6 h|
|Respiratory distress syndrome (RDS)||Premature||+++||N||Diagnostic, but see p. 480||Working diagnosis in all preterm neonates unless chest radiograph suggests alternative. Always consider infection ( Ch. 39.2 )|
|Transient tachynpnoea||FT > premature §||Often caesarean delivery||Mild hypoxaemia needing 40% O 2||+++||R||Diagnostic, but see p. 485||Commonest cause of breathlessness in term babies. By definition, a mild disease ( pp. 485–486 )|
|Meconium aspiration||FT |||Meconium-stained liquor at resuscitation. |
|Meconium-stained baby. |
Meconium in larynx
|+++||N||Streaky||Diagnosis obvious on history. |
Infection may coexist
|Pneumothorax or pneumomediastinum||FT > premature||May be excessive resuscitation at birth||++||R ¶||Diagnostic|
|Massive pulmonary haemorrhage||Premature > FT||Asphyxia or other cause of heart failure, bleeding tendency. Use of artificial surfactant||Crepitations; usually marked pallor. Blood up larynx or in endotracheal tube. PDA after presentation||+||+++||Unhelpful; usually a white-out||Diagnosis based on clinical findings|
|After severe asphyxia||FT **||Severe asphyxia |
|Other features of asphyxia ( Ch. 40.4 )||Marked metabolic acidaemia||++||N||Unhelpful||Tachypnoea driven by acidaemia|
|Infection (pneumonia)||Any||May be helpful||Rarely differentiates this from other causes of dyspnoea||Often severe acidaemia and easy to reduce CO 2 without increasing P aO 2||++||+++||Unhelpful in most cases, though may show patchy changes||Impossible to exclude in any baby ( Ch. 39.2 ). This is the working diagnosis in the absence of specific chest radiograph findings in neonates >6 hours old with respiratory disease. WBC. |
CRP may be helpful
|Congenital malformations||FT > premature||Usually normal delivery. |
May have been detected on antenatal ultrasound
|Rarely helpful||May be profound hypoxaemia with raised CO 2||+++||+||Virtually always diagnostic||Diaphragmatic hernia, cysts, effusions, agenesis all present this way. TOF should not present this way ( Ch. 29.4 )|
|Congenital heart disease||FT > premature||Murmurs, heart size, signs of heart failure||CO 2 normal or reduced. |
In cyanotic CHD P aO 2 rarely >6–7 kPa even in oxygen with IPPV
|R||+++||May be helpful or diagnostic||The alternative common diagnosis in infants presenting after 6 hours and particularly after 24 hours of age. |
ECG and echocardiogram usually diagnostic
|Pulmonary hypoplasia||Any||Prolonged rupture of membranes||No kidneys palpable, amnion nodosum. Dwarf ( p. 581 )||Profound hypoxaemia and hypercapnia||+++||N||Diagnostic; very small lungs||Virtually always rapidly fatal|
|Persistent pulmonary hypertension||FT > premature||May have had mild asphyxia||May hear soft murmur of TI||Gases like cyanotic CHD, i.e. marked hypoxaemia with normal or reduced CO 2||+++||+||Usually normal or nearly so||Can be difficult to exclude cyanotic CHS unless echocardiogram available|
|Inhalation of feed||Any||Obvious||R||+++||Unhelpful||Should not happen in well-run units. Normal term babies rarely inhale, so always seek alternative diagnosis, especially infection|
|Inborn errors of metabolism||FT > premature||May be positive family history or history of unexplained neonatal death in the past||No evidence of lung disease. Tachypnoea driven by acidaemia||Severe metabolic acidaemia, normal P a o 2 ; low P a co 2||R||+++||Often normal||Diagnosis based on blood changes plus ketonaemia in many cases ( Ch. 34.3 )|
|Primary neurological or muscle disease||FT > premature||May be positive family history or history of unexplained neonatal death or infant death. Polyhydramnios may occur||Marked hypotonia. Areflexia, odd face, deformities. No evidence of lung disease||Gases normal (unless apnoeic)||++||++||Often normal||Usually easy to identify as a group|
|Upper airway obstruction||FT > premature||May be typical in choanal atresia ( p. 604 )||Stridor present. Problems resolve on intubation. Laryngoscopy may be diagnostic||Gases normal when intubated; CO 2 may be raised beforehand||++||++||Often normal|
* Mentioning features other than cardinal features of respiratory disease ( pp. 476–477 ).
§ Full-term (FT) greater than premature. This means that the condition can occur at any gestation, but since full-term babies are more common than preterm ones, there are more cases in full-term neonates.
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 ).
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 ).
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 ( ).
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.
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 ( ).
Transportation from the labour ward to the neonatal intensive care unit (NICU)
It is essential to ensure that there is no deterioration in a baby’s lung disease during transfer. All VLBW neonates who require intubation for resuscitation should be ventilated in the transport incubator. Ventilator settings during transport are based on the oxygen saturation and the clinical assessment of the baby, in particular whether there is adequate chest wall expansion. Practice differs regarding whether babies who have been intubated to be given surfactant should be extubated on to nCPAP or remain intubated for transfer and assessment can take place on the NICU. Others do not intubate infants routinely in the labour ward, but transfer babies on nCPAP.
Initial management in the NICU
As soon as the baby arrives in the NICU, he or she must be put into an incubator prewarmed to 35–36°C or placed under a radiant heater. In the next 30–60 minutes, the following procedures should be carried out in all neonates with RDS:
Weigh the infant.
Measure the head circumference to facilitate diagnosis of the rare infant with a subgaleal haemorrhage and subsequently rapidly enlarging head circumference ( Ch. 40.3 ).
Connect to electrocardiogram (ECG) and respiration monitors ( Ch. 19 ).
Measure the baby’s temperature.
Measure P a o 2 , P a co 2 and pH. Consider inserting an indwelling arterial line in babies requiring high oxygen concentrations.
Measure the BP using a continuously recording device once an arterial cannula is in situ, and Dinamap if no cannula is in place.
Treat abnormalities of blood gases ( p. 521 ).
Draw blood for haemoglobin and white cell count. Cross-match all ill neonates, as most eventually need transfusion.
Take a set of cultures, including a blood culture; a lumbar puncture is not required for all infants ( Ch. 39.2 ). A blood sample for culture can be taken from the UAC during the sterile insertion routine.
Send blood for electrolyte measurement: this establishes a baseline and identifies early abnormalities due to problems with maternal fluid balance.
Measure coagulation levels in ill and bruised babies and those less than 30 weeks’ gestation.
Insert a peripheral cannula for the administration of antibiotics.
In critically ill infants or those with extremely low birthweight (ELBW), insert umbilical arterial and venous catheters.
Obtain a CXR, preferably after inserting the UAC.
Give surfactant, if it has not been given prophylactically in the labour ward ( Ch. 13.1 ).
Update the parents.
General management of the baby with RDS
If hypoxic babies are disturbed and handled, their respiration may become very irregular or stop altogether, their right-to-left shunt increases and their P a o 2 falls rapidly. Major disturbances, such as sucking out an ETT, performing a lumbar puncture or taking a CXR, can cause catastrophic falls in P a o 2 . The ‘minimal handling’ maxim dominates the whole approach to managing all sick babies with RDS.
In the first 24–48 hours, secretions are not a problem unless infection develops. As a consequence, chest physiotherapy and routine suctioning of the ETT are contraindicated.
The baby’s thermal environment should be controlled and, if babies are exposed during any procedure, they should be under a radiant heat source, with as much of their surface as possible covered in order to minimise heat losses.
Blood gas management
Abnormalities of P a o 2 , P a co 2 and acid–base metabolism are characteristic of RDS, and keeping the blood gases within a reasonably normal range is the single most important component of the treatment. The detailed management of oxygen administration, CPAP and IPPV are covered on pages 517–523 .
P aO 2
The P a o 2 drawn from a UAC distal to the ductus should be maintained in the range 7–10 kPa (50–75 mmHg). Nowadays many units use pulse oximetry to monitor preterm infants, but the success of maintaining pulse oximeter saturation levels varies between and within centres ( ) and this is not a method of monitoring for very prematurely born infants at high risk of ROP.
P aCO 2
The P a co 2 in a normal newborn baby is in the range 4.6–5.4 kPa (35–40 mmHg). Cerebral blood flow increases about 30% with each 1 kPa increase in P a co 2. . A degree of permissive hypercarbia has been associated with a reduced incidence of BPD ( ) but comparison, however, of P a co 2 target levels of 55–65 mmHg (minimal ventilation) and 35–45 mmHg revealed the latter was associated with a trend towards a higher mortality and neurodevelopmental impairment at 22 months of age ( ). Hypercarbia in the early days of life remains a risk factor for IVH and we advise caution in the use of this approach during the acute phase of RDS ( ; ). Higher P a co 2 levels in more mature neonates with RDS and in <1.50-kg infants more than a week old who are being weaned off IPPV are acceptable, providing the baby is clinically stable with satisfactory pH and base excess levels. Hypocapnia ( P a co 2 <3.3 kPa) should be avoided because of its role in the genesis of PVL ( Ch. 40.5 ). A rapidly rising P a co 2 is a sign of impending respiratory failure, usually associated with a fall in pH, and therefore indicates that the baby should be intubated and ventilated irrespective of postnatal age. More gradual changes with an acceptable pH (>7.25) can be managed conservatively, particularly when the baby is not in the acute phase of illness.
Metabolic alkalaemia is rare and almost always iatrogenic as a result of excessive amounts of intravenous bicarbonate having been given. It requires no therapy. Respiratory alkalaemia is usually due to excessive ventilator pressures.
Acidaemia is common in neonates with RDS. It is always essential to establish whether the acidaemia is respiratory with a raised P a co 2 , or metabolic with a normal P a co 2 and a negative base excess, or a combination of a metabolic and respiratory acidosis, which is more usual. The commonest cause of a metabolic acidaemia in a baby with RDS is a raised lactate from anaerobic metabolism. This in turn can be secondary to hypoxaemia, hypotension, anaemia or infection. When a metabolic acidaemia does develop, it is essential to identify the cause, so direct treatment can be instituted – for example, oxygen for hypoxia, antibiotics for infection, transfusion for anaemia or IPPV for exhaustion.
Acidaemia inhibits surfactant synthesis ( p. 462 ) and increases pulmonary vascular resistance ( ). Once the pH falls below 7.15, other physiological functions such as myocardial contractility ( ) and diaphragmatic activity ( ) begin to deteriorate. The sick neonate has difficulty in excreting an acid load ( ). Ill VLBW neonates should have their pH kept >7.25 at all times. If the pH is <7.25 with a base deficit <10 mmol/l, intravenous alkali therapy is appropriate, if other therapies are not immediately successful. Inappropriately large or fast infusions of base to correct metabolic acidaemia, however, may cause hypernatraemia or cerebral haemorrhage. Two alkalis have been used in neonatal therapy, sodium bicarbonate and trishydroxymethylaminomethane (THAM); both are effective. The theoretical risk that, following infusion of bicarbonate, the cerebrospinal fluid might become even more acidotic does not seem to apply to the neonate. THAM administration does not give a sodium load or increase the P a co 2 and is preferable to bicarbonate if the neonate has a high P a co 2 but apnoea may result and thus THAM should only be given to ventilated neonates. The dose of base to be given is calculated as:
Dose ( mmol ) = base deficit ( mmol / l ) × body weight ( kg ) × 0.4
The rate of infusion should never exceed 0.5 mmol/min. Seven per cent THAM solution contains approximately 0.5 mmol/ml of base.
All neonates suffering from RDS must have their BP monitored regularly ( Ch. 19 ). It is important to determine whether a baby is hypotensive because he or she is anaemic. In general, the first transfusion should be 15 ml/kg given by infusion over 10–15 minutes if the hypotension is severe in the first hours after birth; thereafter, transfusions of blood or albumin are better given more slowly, at a rate guided by the condition of the neonate, clinical response and the BP rise during the transfusion. Transfusions should also be given to babies who are not hypotensive but have features suggesting hypovolaemia, such as poor capillary filling, peripheral vasoconstriction and a falling pH, coupled with the record of large volumes of blood having been removed for analysis. There is, however, no place for routine plasma expanders soon after delivery ( ). If the neonate’s haemoglobin is not low, saline should be given rather than albumin, because the response to albumin is small and rarely sustained ( ) and it has adverse effects. If the hypotensive neonate is severely hypoxic or acidaemic, cardiac function may be impaired and the baby will tolerate volume expansion badly, in which case dopamine is the preferred treatment ( ). Dopamine should also be used in those in whom volume expansion has failed to increase BP; trials have shown it to be more effective than dobutamine ( ; ). The actions of dopamine are complex ( ). At 0.5–2.0 µg/kg/min, dopaminergic actions dilate renal, mesenteric and coronary arteries; from 2 to 10 µg/kg/min, myocardial contractility is increased directly by both α- and β-receptor-mediated actions and also by the release of noradrenaline (norepinephrine) from cardiac adrenergic nerves. At doses above 10–15 µg/kg/min, dopamine begins to show α-adrenergic activity and is a vasoconstrictor of all vascular beds. Initially, therefore, 2–4 µg/kg/min should be given ( ), increasing the dosage until the BP is acceptable.
If plasma volume expansion plus dopamine does not reverse hypotension, other agents can be tried:
Dobutamine. This is an isoprenaline analogue with a primarily β-adrenergic inotropic effect on the myocardium, with little peripheral vascular effect, and no specific effect on the renal vascular bed.
Isoprenaline. This beta-mimetic drug has a chronotropic and inotropic effect and is therefore of greatest benefit if hypotension is accompanied by bradycardia. It is not useful in shock because of its peripheral vasodilator effects.
Adrenaline (epinephrine). This increases BP by peripheral vasoconstriction plus increased myocardial contractility. Its vasoconstrictor effects on the renal vasculature are clearly undesirable.
Dopexamine hydrochloride. This is a synthetic catecholamine with predominant β 2 -adrenergic and dopaminergic activity. In low doses (2–4 µg/kg/min) it can improve BP and urine output ( ), but at higher doses it reduces systemic vascular resistance.
Hydrocortisone 1–2 mg may be successful ( ).
Maintenance of haemoglobin
There are many reasons for a preterm neonate being anaemic ( Ch. 30 ). There may have been an intrapartum haemorrhage, defective placental transfusion or a twin-to-twin or fetomaternal haemorrhage. Blood loss after birth is iatrogenic, but a sudden drop in the haematocrit/haemoglobin level in a baby with RDS suggests the development of a GMH/IVH ( Ch. 40.5 ). Ill neonates, in particular those who are premature, tolerate haemoglobin levels <13 g/dl (packed cell volume (PCV) <40) poorly ( ). This is presumably because of the increase in cardiac output required to meet the oxygen demands of the tissues when there is reduced blood oxygen-carrying capacity. One policy, therefore, is to transfuse all ill neonates when their haemoglobin has fallen below 13 g/dl (PCV <40) ( ). Blood for transfusion should be from a cytomegalovirus-negative donor and be partially packed to a haemoglobin level appropriate for a premature baby (PCV 40–45%), but it does not need to be fresh blood, as the adverse metabolic features of 2–3-week-old donor blood are of no clinical significance when given as a 15 ml/kg transfusion over 30–120 minutes. The blood should be irradiated to avoid the risk of graft-versus-host disease ( Ch. 30 ). If the baby has a clinically important patent ductus, he or she should receive furosemide 1.0 mg/kg during the transfusion; otherwise, there is no need to give diuretic cover. Transfusions may be needed several times a week during the acute phase of the illness and should be continued for as long as the baby is ventilated or has BPD requiring more than 30–40% oxygen. With modern transfusion practice, donor exposure can be reduced to a minimum ( Ch. 30 ).
Routine administration of fresh frozen plasma soon after birth is of no benefit ( ), but it is important to check for coagulation disorders, as these may be of sufficient magnitude to require treatment, particularly in a baby who is small for gestational age ( ).
If an overt coagulation disturbance occurs, such as DIC or thrombocytopenia, this should be treated by appropriate factor replacement ( Ch. 30 ), but it is also essential to control and reverse the underlying problem, such as hypoxaemia or sepsis, which caused the coagulopathy in the first place.
Fluid and electrolyte balance (see Ch. 18 )
Renal function is often impaired in RDS. Urine production may be no more than 1.0–1.5 ml/kg/h, close to the definition of oliguric renal failure (1 ml/kg/h) ( Ch. 35.1 ); however, peripheral oedema is usually due to leaky capillaries. Sodium and potassium do not usually need to be added to the fluid intake for the first 36–48 hours, though the frequent presence of hypocalcaemia in such babies ( Chs. 34.3 and 34.4 ) means that calcium should usually be given ( Ch. 17 ).
Antidiuretic hormone (ADH) levels are raised in babies with RDS, particularly when they are very ill ( ) or after they develop a pneumothorax ( ; ). Babies who develop BPD have particularly raised ADH levels in the first few days after birth ( ). Plasma levels of atrial natriuretic peptide are also high in the first few days in babies with RDS ( ). There is a complex interrelationship between atrial natriuretic peptide levels, ductal shunting with atrial distension in RDS and the postnatal natriuresis that appears to be an integral part of the recovery phase of RDS ( Ch. 18 ) ( ). The increased capillary permeability in RDS results in fluid loss into all tissues, including the lungs.
Analysis of randomised trials demonstrates that restricted water intake significantly increases postnatal water loss and significantly reduces the risk of PDA and NEC ( ). We therefore recommend that infants with RDS should start on 40–60 ml/kg/24 h of a 10% dextrose solution or a suitable ‘standard bag’ of total parenteral nutrition (TPN) to avoid catabolism. For further advice on fluid balance, see Chapter 18 .
Characteristically, diuresis occurs around the time the baby’s lung function improves ( ). Once this happens, previous constraints on the fluid balance to 40–60 ml/kg/24 h need to be relaxed to prevent dehydration, haemoconcentration and worsening jaundice.
Hypoalbuminaemia, with a low colloid osmotic pressure predisposing to tissue oedema, is common in RDS. Infusions of albumin, however, do not improve respiratory function ( ); indeed, they may impair it ( ) and increase the risk of BPD ( ).
Nutrition in RDS
Since the protein and caloric reserves of the VLBW neonate are small, it is essential that some form of nutrition, including protein, is given as soon after birth as possible. Neonates with severe respiratory illness may have an ileus and delayed gastric emptying; bowel sounds are absent and meconium is not passed. Enteral feeding initially may not be feasible in some ventilated babies <1.5 kg or some larger sick neonates. Parenteral nutrition, initially amino acids and glucose, should be given (see Ch. 17 ). There have been anxieties regarding the use of intralipid in neonates with severe lung disease, in whom it may cause a fall in P a o 2 by increasing pulmonary vascular resistance ( ).
Milk in the stomach may compromise ventilation, increase the work of breathing ( ), lower the P a o 2 and even cause apnoea. In spontaneously breathing babies, respiratory problems may be aggravated by the presence of a nasogastric tube obliterating one-half of the upper airway ( ). However, gastro-oesophageal reflux (GOR), NEC and the physiological changes mentioned do not appear to be a major problem in VLBW neonates ( ), even in those who are ventilated and with an indwelling UAC, provided that milk (ideally breast milk; see Ch. 16 ) is only given to babies with clear evidence of bowel activity. Furthermore, there are powerful reasons for attempting to introduce enteral feeds as soon as possible; the prolonged absence of enteral feeding compromises gut growth, the development of enzymes and normal peristaltic activity, and limits early weight gain. The sooner enteral feeding is attempted in VLBW neonates, the sooner full enteral feeding is established ( ; ). Thus, once bowel sounds are present in a ventilated neonate who is appropriately grown and has passed meconium, irrespective of whether or not there is an indwelling UAC ( ), enteral feeding should be started, using if possible the mother’s milk ( Ch. 16 ).
Drug therapy in RDS
It can be difficult to differentiate severe early-onset septicaemia from severe RDS and both conditions may coexist. Without antibiotic treatment, early-onset septicaemia can be fatal within hours ( Ch. 39.2 ). For this reason, all dyspnoeic newborn babies, irrespective of their gestation or CXR appearance, should have appropriate bacterial cultures taken and be treated with antibiotics from the earliest signs of respiratory illness. Penicillin and gentamicin are appropriate therapy as they act synergistically against GBS and are also effective against many of the other organisms that cause early-onset septicaemia and pneumonia. In babies with RDS who are stable or who are improving, antibiotics should be stopped when negative culture results are notified at 48–72 hours.
There have been several trials of diuretics in preterm infants with RDS; no long-term benefits were reported ( ). Diuretics should be reserved for infants who are oliguric and have obvious signs of fluid retention and deteriorating lung function. The response to a dose of 1 mg/kg furosemide should be evaluated. If a diuresis does not result, a combination of furosemide and dopamine may be effective.
Vitamin K should be given to all neonates ( Ch. 30 ).
Pulmonary hypertension should be suspected in infants whose hypoxia is more severe than would be anticipated from their CXR appearance. Administration of pulmonary vasodilators can result in an improvement in oxygenation, but all have side-effects ( p. 498 ). Randomised trials have not demonstrated any long-term benefits of administering inhaled nitric oxide (iNO) to prematurely born infants ( p. 499 ) ( ).
Appropriate analgesia/sedation should be given to ventilated infants (see below and Ch. 25 ) and analgesia administered prior to a painful procedure being undertaken. Sedation is contraindicated in infants with RDS who are breathing spontaneously. Infants who are electively intubated should receive premedication; effective regimes are a combination of atropine, an analgesic (such as fentanyl) and a muscle relaxant (such as mivacurium or succinylcholine) ( ; ).
Methylxanthines are of proven benefit in apnoea of prematurity ( p. 571 ) and in weaning babies less than 30 days old from IPPV ( p. 528 ). Caffeine with its wider therapeutic margin is the agent of choice. In a large randomised trial, caffeine administration was associated with a lower incidence of BPD and better neurodevelopmental outcome ( ). In spontaneously breathing babies with RDS, apnoeic attacks are usually a sign of impending ventilatory exhaustion ( ) and are then an indication for IPPV.
The use of indometacin in preventing or treating a patent ductus is discussed in detail in Chapter 28 .
Surfactant given as ‘rescue’ therapy improves the outcome in babies with established RDS, resulting in a reduction in pneumothorax, mortality and the combined outcome of mortality and BPD ( ; ).
Method of administration
The surfactant preparation is delivered over a period of a few seconds down the ETT. The surfactant usually disseminates homogeneously ( ), particularly if large rather than small doses are used ( ). As might be expected, deposition is influenced by gravity, with dependent parts of the lung receiving more of the dose ( ). There seems, however, to be no benefit from manoeuvres aimed at trying to improve the distribution to different lobes ( ).
To avoid mechanical ventilation, surfactant has been given via a thin ETT to spontaneously breating infants receiving CPAP ( ). In a subsequent observational study, the same centre reported that technique of administration was associated with increases in the use of CPAP and survival without BPD ( ). Appropriately designed trials are required to determine whether such a technique offers long-term advantages.
Mechanism of action
Exogenous surfactant works in two ways: firstly, by coating the alveolar surface and elevating lung volume, thus improving oxygenation and pulmonary perfusion. A fall in PAP and a rise in pulmonary blood flow and left-to-right ductal shunting have been reported in most studies ( ; ), but not all ( ). Secondly, exogenous surfactant administration is incorporated into the type II cells and can provide substrate for, or even stimulate, surfactant production ( ; ).
Size and number of doses
Although beneficial effects, both clinically and physiologically, are seen after a single dose of surfactant, usually in the range of 100 mg/kg ( ; ), most studies show that better results are obtained with more than one dose. The Osiris trial ( ), however, showed no benefit of three or four doses of Exosurf compared with two doses. Meta-analysis has demonstrated that multiple doses give a better outcome than a single dose, with a significant reduction in the pneumothorax rate ( ). Meta-analysis of trials of animal-derived surfactants ( ) demonstrated that multiple doses improved oxygenation and decreased the risk of pneumothorax.
Variation in response
Not all babies respond to surfactant. Factors that lead to an unsatisfactory response include the presence of a PDA, cardiogenic shock or PPHN and airleaks, which in some cases will lead to protein leaking on to the alveolar surface, impairing surfactant function ( ; ). Infants who have been exposed to chorioamnionitis may have a poorer response to surfactant ( ). Failure to respond to surfactant marks out a group of babies with a worse prognosis ( ). Very premature infants may suffer a postsurfactant slump: in an uncontrolled study 70% of affected infants responded to a repeat course after day 6 of life ( ).
Different types of surfactant
Natural surfactants, as they more closely mimic the ‘physiological’ mixture of lipids and proteins (SP-B and SP-C), have a more rapid effect on oxygenation than do synthetic surfactants. Meta-analysis of randomised trials comparing natural and synthetic surfactants demonstrated that the natural surfactant was associated with significant reductions in mortality and pneumothorax and a marginal increase in IVH, but not in grade 3 or 4 IVH ( ). The synthetic surfactant (Lucinactant) containing a polypeptide KL4 composed of lysine and leucine ( ) appears to be as resistant as natural surfactants to the inhibitory effects of proteins on the alveolar surface ( ).
Side-effects during the administration of the surfactant
There may be transient hypoxaemia and bradycardia. There were initial anxieties that, following surfactant instillation, there was either a fall ( ) or a rise in cerebral blood flow velocity ( ) and even an increase in GMH/IVH ( ). Systemic hypotension and a transient flattening of the electroencephalogram (EEG) were also reported ( ; ). More detailed studies have shown little more than a transient perturbation in cerebral haemodynamics, without evidence of cerebral ischaemia, if care is taken with the surfactant instillation ( ; ; ) and the pooled data show either no effect or even a slight reduction in the incidence of GMH/IVH following surfactant administration.
Swamping alveolar macrophages with instilled surfactant could, in theory, increase the baby’s susceptibility to infection ( ), but no clinical evidence has been found of such an association. Anxiety has been expressed that immune responses to exogenous surfactant proteins instilled into the lung would cause short- or long-term problems, but none has been reported. Surprisingly, antibodies to surfactant proteins have been found in both surfactant- and placebo-treated infants ( ).
Pulmonary haemorrhage (MPH), particularly in ELBW neonates, has been noted following surfactant administration, this was increased (doubled) with the use of a synthetic surfactant (Exosurf) ( ; ).
Follow-up studies have not demonstrated any additional neurological deficits in surfactant-treated survivors ( ; ) nor any increase in severe ROP ( ). Surfactant-treated infants may have improved long-term lung function compared with untreated controls ( ; ).
The general principles of monitoring the ill preterm neonate are laid out in Chapter 19 .
Many of the complications are dealt with in detail elsewhere and will be only briefly summarised below.
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.
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 .
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.
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%.
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.
The most important respiratory sequel of RDS is BPD ( Ch. 27.3 ). Airway problems secondary to prolonged intubation may also occur ( p. 610 ). After discharge, babies who have survived RDS in the neonatal period are more likely to have respiratory illness, particularly in the first year after birth, than are infants born at term or prematurely without respiratory problems. Preterm babies have lung function abnormalities at follow-up: an increased airways resistance and air trapping. These sequelae are more common in neonates who required prolonged ventilation and they are particularly severe in those who developed BPD ( Ch. 37.3 ).
Long-term neurological sequelae
See Chapter 3 .
Transient tachypnoea of the newborn
This is between 4 and 5.7 ( ) per 1000 infants delivered between 37 and 42 weeks of gestation. TTN does occur in prematurely born infants, although coexisting problems such as RDS may mask the presentation; an incidence of 10 per 1000 has been reported in all babies born in 65 hospitals ( ), which is higher than in term infants.
TTN is due to a delay in fetal lung fluid clearance ( ). It is more common in infants who are born by caesarean section without labour ( ). In babies who develop TTN, noradrenaline (norepinephrine) levels are lower than in those delivered following labour ( ). In the absence of labour, anticipatory lung fluid clearance has not occurred ( p. 449 ) ( ).
The relative risk for respiratory distress after birth by caesarean section without labour has been reported to be 1.74 if delivery occurs at 37 rather than 38 weeks of gestation ( ). Similarly, TTN and RDS were found to be more common in twins delivered by caesarean section if this was performed prior to 38 weeks of gestation ( ). Others ( ), however, have suggested that respiratory morbidity may only be increased by delivery by caesarean section if this occurs prior to the 36th week of gestation.
Respiratory distress after elective caesarean section in babies born at term may be due to surfactant deficiency per se ( ), but surfactant deficiency may also be important in the pathogenesis of TTN ( ). Other risk factors for TTN include male sex ( ; ) and a family history of asthma ( ; ; ). The proposed mechanism for the association of TTN and maternal asthma is that infants of asthmatic mothers have a genetic predisposition to β-adrenergic hyporesponsiveness ( ). Resorption of fetal lung fluid is a catecholamine-dependent process; it has been reported ( ) that beta 1 and 2 adrenoreceptor polymorphisms, known to alter catecholamines, are operative in TTN. NO polymorphisms were not detected in the second transmembrane-spanning domain of the epithelial sodium channel ( ).
The classical presentation is isolated tachypnoea with respiratory rates up to 100–120/min. The infants rarely grunt, which is a sign indicating atelectasis. Retraction, indicating non-compliant lungs, is minimal. The chest may be barrel-shaped as a result of hyperinflation, and the liver and spleen are palpable because of downward displacement of the diaphragm. Peripheral oedema is often present and affected babies lose weight more slowly than controls ( ). On auscultation, there may be added moist sounds, similar to those heard in heart failure. Tachycardia is common, but the BP is usually normal. TTN usually settles within 24 hours, but may persist for several days. Some infants with TTN have been reported to require high concentrations of supplementary oxygen ( ), even 100% oxygen for several days ( ) or IPPV ( ), but whether such patients had TTN is arguable.
Affected infants usually have a mild hypoxia; a marked respiratory or metabolic acidosis is unusual, and, if present, makes a review of the diagnosis mandatory. The CXR shows hyperinflation, prominent perihilar vascular markings, oedema of the interlobar septa and fluid present in the fissures ( ) ( Fig. 27.15 ). The prominent perihilar streaking is due to engorgement of the periarterial lymphatics, which participate in the clearance of lung fluid; fluid may also be present in the costophrenic angles. The CXR usually clears by the next day, although complete resolution may take 3–7 days. Lung ultrasonography shows a difference in lung echogenicity between the upper and lower lung areas in infants with TTN; comet-like tails have been seen in the inferior fields, which were not seen in the healthy controls ( ; ). Infants with TTN have a reduced tidal volume, but a raised minute volume due to the increased respiratory rate. Compliance is reduced; airways resistance and FRC are raised ( ).
A rapid respiratory rate may be due to cerebral irritation from subarachnoid blood or perinatal hypoxic ischaemia ( Ch. 40.3 ), but these infants are distinguished by their history and the presence of a respiratory alkalaemia. The CXR appearance of TTN may be mimicked by heart failure. If the heart failure is due to asphyxia, there will be a positive history and the heart will usually be enlarged; if it is due to congenital heart disease, a murmur may be present. It is not possible to differentiate TTN from early-onset sepsis ( Ch. 39.2 ) and this needs to be considered when planning the initial treatment.
Continuous infusion of terbutaline given to mothers prior to elective caesarean section was associated with improved lung function in their offspring ( ), but the mothers who received terbutaline had significantly higher levels of bleeding.
Most infants with TTN require no form of respiratory support other than added oxygen and rarely require an inspired oxygen concentration greater than 40% or support for more than 3 days. Intravenous penicillin and gentamicin should be administered until infection has been excluded ( Ch. 39.2 ). Hydration should be maintained with intravenous glucose electrolyte solutions, and nasogastric tube feeds withheld until the respiratory rate settles. Diuretics are of no proven benefit ( ; ). In a randomised trial, although infants who were given oral furosemide 2 mg/kg followed by 1 mg/kg 12 hours later lost more weight than the placebo group, there were no significant differences between the two groups with regard to the durations of tachypnoea or hospitalisation or the severity of symptoms ( ).
The standard monitoring outlined in Chapter 19 should be applied. A UAC should be inserted if the baby has a persisting requirement for more than 40% oxygen.
These are rare, though airleaks may occur, particularly if the baby requires CPAP or IPPV.
The condition is self-limiting, although the symptoms may last throughout the perinatal period. There is debate whether babies who have had TTN are more likely to wheeze at follow-up ( ; ).
Minimal respiratory disease
Minimal respiratory distress is usually diagnosed if transient respiratory signs persist for less than 4 hours ( ).
Some babies are hypothermic, with a temperature of less than 35°C. Surfactant function is temperature-dependent ( ) and the babies often improve within an hour or two when their temperature returns to normal. Some babies have a moderately low pH at 7.20–7.25, which may transiently compromise surfactant synthesis ( ). The tachypnoea may be the result of mild intrapartum asphyxia with or without minor degrees of aspiration of meconium or amniotic squames. In most cases, the condition probably represents the very mild end of the spectrum of delayed clearance of lung liquid, which in the more marked form is diagnosed as TTN.
The baby, near or at term, presents within the first 2–3 hours, commonly after being transferred to the postnatal ward with the mother. The infant usually has an expiratory grunt, which may be quite loud; there is mild sternal or intercostal recession and a respiratory rate of up to 80–100/min. Cyanosis, if present, is relieved by administering 25–30% oxygen. There are no added sounds in the chest and the rest of the clinical examination is normal.
This is always a retrospective diagnosis, made once the baby has recovered and shows no signs of infection or more serious pulmonary disease. The major anxiety when the baby first presents is whether the diagnosis is early-onset sepsis ( Ch. 39.2 ). In some infants with mild pulmonary hypoplasia tachypnoea is the only presenting feature ( ); such cases, however, can be distinguished by the persistence of the tachypnoea, small-volume lungs on CXR and abnormal lung function tests.
It is advisable to check the infant’s blood gas, take a CXR to exclude other diagnoses and undertake a blood count and blood culture. Hypoglycaemia should be excluded, particularly if the baby’s mother has diabetes or the baby is small for dates. The blood gas analyses will usually show mild hypoxaemia in air ( P a o 2 6–8 kPa, 45–60 mmHg), which rapidly becomes normal in 25–30% oxygen; P a co 2 and the pH will usually be normal or there will be a mild metabolic acidaemia, with a pH of 7.20–7.25 and a base deficit of 10 mmol/l. The haemoglobin and white cell count will be normal. The CXR, particularly if taken within 1–2 hours of birth, often shows some streakiness or a rather non-specific haziness, both of which probably represent delayed clearing of the fetal lung liquid, but this is not an indication for an early CXR, i.e. before 4 hours ( p. 480 ).
Antibiotics should be given to all infants with respiratory distress, as infection cannot be excluded until the results of the cultures are available at 48 hours after birth.
The prognosis is excellent. Most babies are asymptomatic by 12 hours of age.
Pneumothorax and pulmonary interstitial emphysema (PIE) are the most common forms of airleaks in the newborn; pneumomediastinum, pneumopericardium and pneumoperitoneum also occur. Rarely, multiple airleaks may be complicated by subcutaneous emphysema and systemic air embolism.
Pulmonary airleaks occur when there is uneven alveolar ventilation, air trapping and high transpulmonary pressure swings; the final common pathway is alveolar overdistension and rupture. Uneven ventilation is compounded by a lack of redistribution of pressure through the alveolar connecting channels, the pores of Kohn, which are reduced in number in the immature lung ( ). The rupture is thought to occur at the alveolar bases, in apposition to blood vessels. The gas tracks along the sheaths of pulmonary blood vessels to the mediastinum, where it accumulates in the roots of the lungs; air may then rupture into the pleura, mediastinum, pericardium or extrathoracic areas. The existence of PIE supports this hypothesis, as, after alveolar rupture, gas is trapped in the parenchyma by the extensive connective tissue matrix and increased interstitial water in the preterm lung. This prevents decompression into the mediastinum, thereby splinting the lung and compressing the blood vessels. An alternative hypothesis is that interstitial air directly enters the pleural cavity after rupture of a subpleural bleb ( ).
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.
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) ( ).
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 ).
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 ).
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 ).
Breathing out of phase with the ventilator during IPPV increases the incidence of pneumothorax (see above). Neuromuscular blocking agents should only be given selectively, that is, to infants who are actively expiring against the ventilator ( ). Meta-analysis of six trials in which routine neuromuscular paralysis was compared with no routine paralysis demonstrated that no significant difference was found in airleak, mortality or BPD, but there was a signicant reduction in IVH ( ). In subgroup analysis of trials in which a selected group of infants with evidence of asynchronous respiratory effort were studied, there was a significant reduction in IVH of all grades and a trend towards less airleak ( ). It was concluded, therefore, that for ventilated preterm infants with evidence of asynchronous respiratory effort, neuromuscular paralysis with pancuronium seems to have a favourable effect on IVH and possibly on pneumothorax. Active expiration may be difficult to detect clinically at slow rates; however, if a neonate’s oxygenation fails to improve and obvious respiratory efforts continue as the ventilator rate is increased to 60–80/min, this identifies the majority of neonates with a persisting active respiratory pattern who are likely to benefit from paralysis ( ). Infants who receive neuromuscular blocking agents, such as pancuronium, require higher peak pressures when the first dose is given, to maintain oxygenation; ventilator rates should be reduced to <60/min to avoid gas trapping ( ). Other neuromuscular blocking agents include vecuronium, atracurium and cistracurium. A single dose of vecuronium has been shown to reduce hypoxaemic episodes without impairing lung function ( ).
Many clinicians prefer to avoid use of neuromuscular blocking agents and administer analgesics and/or sedatives to try and suppress respiratory activity, but also to minimise any discomfort felt by a ventilated baby ( Ch. 25 ). Stress hormone levels have been demonstrated to be significantly related to the severity of illness and to fall with sedation ( ). Administration of analgesics and/or sedatives, although having benefits, has not been demonstrated in randomised trials to reduce the pneumothorax rate ( ) and they have side-effects. In a randomised trial ( ), fentanyl administration was associated with a reduction in stress markers, but no improvements in long-term outcome. Fentanyl can cause muscle rigidity and precipitate movement disorders, and withdrawal symptoms can occur. Plasma fentanyl clearance increases with maturity; thus gestational age should be taken into account when prescribing fentanyl ( ). Naloxone is an effective antidote to fentanyl. Morphine, compared with placebo, significantly reduced adrenaline (epinephrine) concentrations in ventilated neonates, but did not influence the occurrence of airleak ( ). Morphine does not appear to be associated with adverse effects on intelligence, motor function or behaviour at follow-up ( ), but should be used with caution in prematurely born infants, because of its low clearance, which correlates with gestational age ( ). In a large ( n = 898) randomised trial ( ), morphine infusion did not improve short-term pulmonary outcomes amongst ventilated infants and additional analgesia with morphine was associated with more airleaks and longer durations of high-frequency ventilation, nasal CPAP and oxygen therapy. In addition, secondary data analysis from that randomised trial demonstrated that use of morphine delayed the attainment of full feeds, partly by delaying the start of feeding, although its use did not increase gastrointestinal complications ( ). Diamorphine may be preferable to morphine, as in a randomised trial ( ) both agents reduced the stress response to ventilation, but diamorphine had a more rapid onset of sedation and did not have morphine’s tendency to increase hypotension. Midazolam is sedative in ventilated babies ( ), but it does not influence the course of RDS and in high doses it causes respiratory suppression, hypotension and reduced cerebral blood flow. Long-term use can result in accumulation and an encephalopathic illness has been described. Midazolam is reversed by flumazenil. Midazolam is not as effective a sedative as chloral ( ), but chloral can cause gastric irritation and its metabolite is hepatotoxic.
Modes of ventilation
High-frequency positive-pressure ventilation
Ventilating babies at rates of >60/min rather than at 30–40/min reduced the incidence of airleaks ( ; ). Those data were subsequently confirmed by the results of two multicentre randomised studies ( ; ). Meta-analysis of the results of the randomised trials ( ) demonstrated that the risk for airleak at the faster compared with the slower rate was significantly reduced. The most likely explanation for the reduction in airleak at the faster frequency was that spontaneous respiration synchronises with the ventilator at fast rates ( ), whereas infants actively expire at slow rates. There have, however, been no randomised trials comparing different ventilator rates in infants routinely exposed to antenatal steroids and postnatal surfactant; whether fast rates are more effective than slow rates in preventing pneumothoraces in such a population remains unknown.
Meta-analysis of the results of randomised trials demonstrated that the incidence of airleak was not reduced by use of patient-triggered ventilation (PTV) ( ). During pressure support ventilation (PSV), both the initiation and termination of ventilator inflation are determined by the infant’s respiratory efforts. PSV does reduce the rate of asynchrony ( ), but a reduction in the incidence of pneumothorax has not been reported.
Meta-analysis of the results of randomised trials has demonstrated that high-frequency oscillation (HFO) does not reduce the incidence of pneumothorax in preterm infants ( ). In a randomised trial ( ), use of HFO was associated with a reduction in the incidence of pneumothorax, but this was at the expense of an increase in intracerebral haemorrhage (ICH).
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.
A large tear in the pleural surface of the lung, a bronchopleural fistula, may not close with conventional tube drainage of the pneumothorax. Alternative strategies are surgical closure at thoracotomy ( ), selective bronchial intubation (see below) ( ) or instillation of fibrin glue into the pleural space ( ).
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.
Pulmonary interstitial emphysema
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.
There is an inverse relationship between the incidence of PIE and birthweight ( ).
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.
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.
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.
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.
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 ( ; ; ).
Pneumomediastinum occurs in approximately 2.5 per 1000 livebirths, in those babies with gas trapping associated with RDS, pneumonia, MAS and mechanical ventilation.
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 ).
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 ( ).
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.
A pneumopericardium usually causes cardiac tamponade with sudden hypotension, bradycardia and cyanosis. The heart sounds are muffled, but a friction rub is rarely audible. The signs may be confused with those of a tension pneumothorax, but the CXR is diagnostic ( Fig. 27.27 ). It is usually accompanied by other major airleaks such as pneumomediastinum, widespread PIE or tension pneumothorax.
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.
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.
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.
The mortality rate for symptomatic pneumopericardium is between 80% and 90% ( ) and many survivors have neurological sequelae.
This may result from perforation of the gut, but may also be caused by air dissecting from the chest through the diaphragmatic foramina into the peritoneum ( ) ( Fig. 27.28 ), particularly in ventilated babies who already have a pneumothorax and a pneumomediastinum. In some cases, the gas localises in the connective tissue on the posterior wall of the abdomen, a pneumoretroperitoneum ( ).
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.
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.
Systemic air embolism
This is a rare complication of IPPV. Affected infants are usually premature, have severe pulmonary insufficiency necessitating very high ventilator pressures (>40 cmH 2 O) and the majority (94%) have other airleaks ( ). This condition has, however, been reported in infants supported by CPAP ( ). It is associated with a sudden and catastrophic deterioration in the baby’s condition, with pallor or cyanosis, hypotension and bizarre ECG irregularities.
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.
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.
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.
This condition is usually fatal ( ).
This condition, with air tracking into the neck or other subcutaneous tissues, is usually associated with a pneumomediastinum. It requires no treatment. A localised subcutaneous collection of air under tension – a bronchocutaneous fistula – has been described ( ).
Persistent pulmonary hypertension of the newborn
The dominant pathophysiological feature of PPHN is a high PAP. This condition has been called persistent fetal circulation, but this term should be avoided, as one of the characteristic features of the fetal circulation, the high-flow, low-resistance circuit through the placenta, is missing.
Definition and classification
Persistent fetal circulation syndrome was first used by to describe babies who had a structurally normal heart, but large right-to-left shunts at atrial and ductal levels secondary to pulmonary hypertension. It is now understood that PPHN is the common endpoint of several different pathophysiological mechanisms. PPHN is present when an infant with an echocardiographically confirmed structurally normal heart has:
severe hypoxaemia, usually a P a o 2 5–6 kPa (37.5–45 mmHg) in an F I o 2 of 1.0 and IPPV if necessary
mild lung disease, but the hypoxaemia is disproportionately severe for the radiological, clinical and acid–base abnormalities
evidence of a right-to-left ductal shunt (usually a P a o 2 in the distal aortic (UAC) blood 1–2 kPa (7.5–15 mmHg) lower than simultaneous preductal (right radial artery) P a o 2 estimation); in the absence of a ductal shunt; a large shunt may be demonstrated echocardiographically at the foramen ovale ( ).
There are a number of distinct syndromes which can result in a baby developing PPHN:
Primary PPHN or PPHN in the presence of mild neonatal lung disease. Those with primary disease are the babies originally described by who are profoundly hypoxic but have no clinical or autopsy evidence of lung disease. This entity merges into PPHN in babies who have disproportionately severe hypoxaemia from what appears clinically, radiologically and on P a co 2 measurements to be mild parenchymal lung disease. There is now considerable evidence to suggest that this entity is due to excessive muscularisation of the pulmonary arterial system starting in the antenatal period (see below), perhaps aggravated by perinatal asphyxia ( ).
PPHN secondary to severe perinatal asphyxia. In these babies, hypoxia and acidaemia, both of which are powerful pulmonary artery constrictors ( ), prevent the normal postnatal changes in circulation. The tendency to PPHN may be increased in such neonates by similar structural changes in the vasculature to those outlined above and the large right-to-left shunt may be aggravated by systemic hypotension secondary to postasphyxial myocardial damage ( ).
PPHN secondary to infection. This particularly severe form of the disease, characteristically associated with GBS sepsis, is probably due to the release of vasoactive substances.
PPHN secondary to pulmonary hypoplasia. This is characteristic of neonates with diaphragmatic hernia, and is due to the abnormal development and reduced cross-sectional area of the pulmonary vasculature ( ).
PPHN secondary to drug therapy. This has been reported after the use of prostaglandin synthetase inhibitors before delivery. One survey demonstrated that mothers of inborn term babies with PPHN were 9.6 times more likely to have taken aspirin in pregnancy and 17.5 times more likely to have taken other prostaglandin synthetase inhibitor drugs ( ). These drugs, either by a direct effect on the pulmonary vasculature or by closing the fetal ductus, cause fetal pulmonary hypertension which persists postnatally ( ; ). It is probably the result of changes in the pulmonary arterial musculature similar to those reported in primary PPHN ( ) ( Fig. 27.32 ). Administration of ibuprofen, a cyclo-oxygenase inhibitor, in the first 6 hours after birth has been associated with the development of pulmonary hypertension ( ).
PPHN secondary to alveolar capillary dysplasia. Several reports have appeared of babies with clinical PPHN in whom, at postmortem, there appeared to be misalignment of the pulmonary vessels and poor apposition of the vessels to the alveoli ( ). This condition is fatal and does not respond to extracorporeal membrane oxygenation (ECMO) ( ).
PPHN secondary to congenital heart disease. Conditions that obstruct the venous outflow from the lungs or cause myocardial failure can cause pulmonary hypertension and/or marked right-to-left shunting with hypoxaemia. They are considered in detail in Chapter 28.
Iatrogenic PPHN secondary to overventilation ( p. 517 ).
The pathognomonic feature of this condition is the presence of pulmonary hypertension, producing right-to-left shunts at the level of the ductus arteriosus and the foramen ovale ( ; ). The comparatively small difference between pre- and postductal P a o 2 levels, rarely greater than 2–3 kPa (15–21 mmHg), however, suggests that only a small component of the shunt occurs at duct level and the majority is through the foramen ovale ( ). PAP is at or above systemic levels. have shown that a marked reduction in left ventricular function is a significant marker of severe disease.
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 ( ).
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.
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.
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 ( ).
Familial cases have been reported.
In babies with primary PPHN, the presentation is often subtle and may mimic that of cyanotic congenital heart disease. Babies with primary PPHN virtually always present within 12 hours of birth and very rarely after 24 hours. In PPHN which is secondary to pre-existing lung disease, the clinical features will be those of GBS sepsis ( Ch. 39.2 ), RDS ( p. 476 ) or MAS ( p. 503 ), together with the cyanosis of severe PPHN. Secondary effects from the hypoxia, such as acidaemia and hypotension, may be present. The age at diagnosis still depends on the underlying problem and its severity. In GBS infection ( Ch. 39.2 ), severe asphyxia ( Ch. 40.4 ) and congenital diaphragmatic hernia (CDH; ), PPHN will appear within 6 hours of birth in a critically ill neonate.
The baby remains cyanosed even when high oxygen concentrations are administered by IPPV. Respiratory distress, however, is often mild. The respiratory rate is usually increased to 60–100/min; the higher rates are seen in term babies. Retraction is mild, grunting rare and the air entry is normal. The heart rate is normal or slightly increased. All pulses, including the femorals, are normal. The first heart sound is normal, but the second is commonly single and loud because of the rise in PAP. There is a right parasternal heave and a soft systolic murmur may be heard, signifying tricuspid incompetence or, occasionally, mitral incompetence. Heart failure is not usually present, but the infant may be hypotensive. Examination of the abdomen, genitourinary system and the central nervous system is usually normal in the absence of predisposing factors such as sepsis or asphyxia.
Cyanotic congenital heart disease, which presents in the first 12 hours, is usually a severe form, with heart failure, distinctive murmurs and obvious changes on the CXR and ECG. In PPHN, however, the CXR and ECG are often within the normal limits, and the findings on examination of the cardiovascular system are comparatively subtle (see above).
Echocardiography will establish the normal cardiac anatomy in PPHN. The response to ventilation with 100% oxygen may differentiate PPHN from cyanotic congenital heart disease ( ). In the former, the P a o 2 will usually increase to >13 kPa (100 mmHg), whereas in cyanotic heart disease it will not rise above 5–6 kPa (37.5–45 mmHg). Not all neonates with PPHN, especially those with sepsis and CDH, however, respond in this way.
Haematological and biochemical
Thrombocytopenia has been reported in severe cases ( ); it may be a manifestation of abnormal prostaglandin activation.
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.
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.
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 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 ( ).
PPHN can be secondary to sepsis; thus it is important that the infant is screened for infection ( Ch. 39.2 ).
The treatment of PPHN can be divided into two components: that of the hypoxaemia and PPHN and that of the coexisting lung disease, which is covered elsewhere.
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.
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.
Broad-spectrum antibiotic cover should be given to all babies with PPHN.
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
This was described first by . Reduction of the P a co 2 to 2.5–3.5 kPa (19–26 mmHg) and elevation of the pH to 7.55–7.60 resulted in a rise in P a o 2. Hyperventilation is no longer advocated, because a P a co 2 of 2.5–3.5 kPa (19–26 mmHg) results in a 50% reduction of cerebral blood flow, which could cause cerebral ischaemia. Although in babies born at term no long-term adverse sequaelae have been described, hypocapnia in preterm babies has been linked to PVL ( ; ) and marked hypocapnia (2.5 kPa (19 mmHg)) may reduce cardiac output ( ). Hyperventilation, via barotrauma, may also result in airleaks ( ) and BPD ( ; ). In addition, persisting hypocapnic alkalaemia markedly increases the hypoxic reactivity of the pulmonary vasculature, thus tending to perpetuate the pathophysiology of PPHN ( ).
High-frequency oscillation: jet ventilation
Anecdotally, these forms of respiratory support have been associated with improvements in oxygenation ( ; ; ).
Extracorporeal membrane oxygenation
ECMO is an effective rescue therapy for infants with PPHN ( ) (see p. 525 ).
Tolazoline is no longer the drug of choice for PPHN. Between 25% and 50% of babies with primary PPHN or PPHN secondary to RDS or MAS respond to this agent, but the effects on the systemic circulation are at least as great as those on the pulmonary vasculature, and side-effects, including significant hypotension, are common. Other side-effects have been reported and include renal failure and gastrointestinal haemorrhage ( ). Side-effects may be minimised by a dilute, slow infusion ( ), but we recommend that iNO be considered first.
Prostacyclin (PGI 2 ) affects vascular tone by increasing cAMP levels. This agent, in doses of 5–40 ng/kg/min, is an effective pulmonary vasodilator, but has a wide list of side-effects ( ).
Endotracheal administration of tolazoline ( ) or PGI 2 ( ) can cause selective vasodilation. Inhalation of PGI 2 in animals and babies has been shown to be at least as effective as the parenteral preparation, with fewer side-effects, and to cause an equivalent response to iNO ( ; ). High doses of aerosolised PGI 2, , however, could spill over into the systemic circulation, and thus the magnitude of the dose administered is critical if this therapy is to be a selective pulmonary vasodilator.
Iloprost is a PGI 2 analogue; it has advantages over PGI 2 in that it has a longer half-life and does not need to be dissolved in an alkaline solution, which is potentially damaging to the lung. There are case reports of it improving oxygenation in infants poorly responsive to iNO ( ).
As a loading dose of 200 mg/kg followed by an infusion of 20–100 mg/kg/h, it is effective ( ; ) but less so and with more side-effects than iNO ( ). During magnesium therapy, levels must be carefully monitored, as hypermagnesaemia can cause sedation, muscle relaxation, hyporeflexia, and calcium and potassium disturbances. Magnesium sulphate has not been assessed in appropriately designed randomised trials; its use cannot therefore be recommended ( ).
Inhaled nitric oxide
NO is a vasodilator substance that relaxes vascular smooth muscle. It is synthesised in the endothelial cells from l -arginine and oxygen ( ). Neonates who suffer from PPHN may have low levels of arginine ( ), but this is not a universal finding ( ). NO diffuses into the smooth-muscle cells, where it activates guanylate cyclase to increase 3,5-GMP and hence produces relaxation of the smooth muscles. When NO is inhaled, it diffuses across the alveolar capillary membrane and activates guanylate cyclase in the pulmonary arteriolar smooth muscle. The resulting increase in cGMP causes smooth-muscle relaxation. NO then binds rapidly to haemoglobin; once bound, it is inactivated and therefore produces no systemic effects.
Since the preliminary studies of and , there have been many reports of the benefit of NO in PPHN. The efficacy of iNO is improved if it is combined with a strategy to improve lung volume ( ; ). iNO can be delivered with either HFJV or HFOV ( ). In infants with PPHN and severe lung disease, the combination of HFOV and iNO is better than iNO or HFOV alone ( ). Even in patients with moderate PPHN, iNO can increase arterial oxygenation and reduce the amount of ventilatory support required ( ). Not all term babies, however, respond: a poor response has been seen in those with severe parenchymal disease, systemic hypotension and myocardial dysfunction, as well as in those with structural pulmonary abnormalities, for example infants with pulmonary hypoplasia or dysplasia, who can develop a sustained dependence on iNO ( ).
In term-born babies, meta-analysis of the results of nine randomised trials demonstrated that use of iNO was associated with an improvement in oxygenation and a reduction in the combined outcome of death or need for ECMO; the effect was due to a reduction in the need for ECMO ( ). No excess of adverse neurodevelopmental outcomes has been demonstrated in babies exposed to iNO in randomised trials ( ; ; ). No significant long-term benefits of iNO have been demonstrated in babies with CDH and they have a higher incidence of sensorineural hearing loss (Neonatal Inhaled Nitric Oxide Study Group 1997).
Meta-analysis of 11 randomised trials demonstrated that the effect of iNO in preterm babies depends on the timing of administration and the population ( ). Early rescue treatment based on oxygenation criteria did not affect mortality or BPD rates and there was a trend towards an increase in ICH. Early, routine use for intubated infants, however, was associated with a just significant reduction in the combined outcome of death or BPD (relative risk (RR) 0.91, 95% confidence interval (CI) 0.84–0.99) and a reduction in the incidences of severe ICH and PVL (RR 0.70, 95% CI 0.53–0.91). One study, however, was from a single centre ( ) and in the other ( ) the positive effects were only in infants with a birthweight between 1000 and 1250 g. In a subsequent large trial ( n = 800), in which preterm infants were randomised to early, prolonged, low-dose iNO therapy, no significant differences were demonstrated in any important outcomes ( ). In the meta-analysis, overall use of iNO after 3 days based on an elevated risk of BPD showed no effect on BPD ( ). In one trial ( ), however, the rate of survival without BPD at 36 weeks’ postmaturational age was higher in the iNO group, who were also discharged home sooner and received supplementary oxygen for a shorter time ( ). At follow-up of that trial, the iNO-treated infants received significantly less bronchodilators, inhaled and systemic steroids, diuretics and supplemental oxygen after discharge, but there were no significant differences in the rates of rehospitalisation or wheezing ( ).
Studies in term infants have demonstrated that levels of 5 ppm may be equally as effective as higher doses ( ; ), but lower doses (2 ppm) are not ( ). Indeed, initial treatment with a subtherapeutic dose of iNO may diminish the clinical response to higher doses and have adverse sequelae ( ). It has been recommended to start at 20 ppm in term newborns with PPHN; increasing to 40 ppm does not generally improve oxygenation in infants who have failed to respond to 20 ppm ( ). iNO can be delivered during transport; the method of delivery is influenced by the mode of transport either by road or by air ( ).
NO has a very short duration of action; thus, rebound vasoconstriction and hypoxaemia can result if the NO is suddenly withdrawn. Therefore, to prevent sudden withdrawal of NO during routine nursing procedures, in-line suction devices are recommended to prevent interrupting the circuit and handbagging circuits should contain an additional iNO source. It is important to wean iNO as soon as oxygenation has improved and the baby has stabilised, otherwise tolerance may occur. During weaning from iNO, the level should be gradually reduced; decreasing to 1 ppm minimises the deterioration in oxygenation ( ). Increasing the inspired oxygen concentration by 10–20% immediately prior to cessation of iNO may also be helpful. Scavenging is not necessary in a well-ventilated environment (8–12 air changes per hour) but, even so, environmental checks are recommended to reassure staff that accidental macrocontamination has not occurred. See above: it is essential to exclude congenital heart disease in neonates being considered for iNO.
Infants at or near term with hypoxic respiratory failure (an oxygenation index of at least 25) should be considered for iNO, but only after their lung volume has been optimised and their cardiovascular status stabilised. Neonates who are hypoxaemic secondary to congenital heart disease, right ventricular-dependent circulation, severe left ventricular dysfunction, duct-dependent circulation or methaemoglobinaemia should not be given iNO. There is currently insufficient evidence to recommend routine use of iNO in prematurely born babies or in term babies with CDH.
NO should be administered only if continuous NO and nitrogen dioxide (NO 2 ) monitoring are available and there is immediate access to methaemoglobin analysis ( ). NO reacts rapidly with O 2 to form NO 2 , which is toxic to the lung. The nitrosylhaemoglobin produced by NO binding to haemoglobin is rapidly converted to methaemoglobin, which is then reduced by methaemoglobin reductase in erythrocytes. Unfortunately, immature infants and those of certain ethnic groups have low levels of methaemoglobin reductase. Particularly in VLBW babies with RDS ( ), care needs to be taken that NO 2 is not being formed ( ), and that the baby is not developing methaemoglobinaemia ( ; ). These problems are more likely if high concentrations of NO ( ) are used for prolonged periods in high inspired oxygen concentrations ( ). Inhaled NO administration has been associated with an increased bleeding time ( ). It seems prudent to try to avoid iNO therapy in babies with a low platelet count or a bleeding diathesis, until these have been treated.
Phosphodiesterases (PDEs) are enzymes which catalyse the hydrolytic cleavage of the 3’ PDE bond of the cyclic nucleotides (cGMP and AMP), which play a central role in pulmonary vascular smooth-muscle relaxation. PDE inhibitors which have been used to treat neonates with pulmonary hypertension include dipyridamole (a non-specific PDE 5 inhibitor), milrinone (a PDE 3 inhibitor) and sildenafil (a PDE 5 inhibitor). Milrinone administration has been associated with improvement in oxygenation in neonates unresponsive to iNO ( ; ), but some of the infants developed severe ICH ( ). In animal models of pulmonary hypertension, sildenafil (a PDE 5 inhibitor) was more effective than iNO in the treatment of pulmonary hypertension ( ). Sidenafil has been shown selectively to reduce pulmonary vascular resistance in both animal models and humans. It produces vasodilation by increasing cGMP by inhibiting the PDE involved in degradation of cGMP to guanosine monophosphate ( ). In a small trial, infants with oxygen index (OI) >25 were randomised to receive oral sildenafil (1 mg/kg 6-hourly) or placebo; the infants who received sildenafil experienced an improvement in oxygenation. Six of seven sidenafil-treated infants survived compared with only one of the six controls ( ). Despite the limited evidence available, sildenafil is being increasingly used ( ). Sildenafil has been used to support infants as they are being weaned off iNO ( ).
Calcium channel antagonists
Diltiazem has reduced right ventricular pressure in neonates with PPHN ( ).
Endothelin receptor antagonists
Bosentan is an orally active dual endothelin receptor antagonist (ETA and ETB) and has been shown to reduce PVR and pulmonary arterial pressure in pulmonary hypertension in adults. Successful use in infants is limited to a few case reports ( ).
Inhaled ethyl nitrite gas
Inhaled O-nitrosoethanol gas administered to seven babies with PPHN produced sustained improvements in oxygenation, without adverse effects ( ).
Monitoring babies with persistent pulmonary hypertension of the newborn
This has to be meticulous and continuous. An indwelling continuously recording P a o 2 cannula should be placed in the aorta, but the umbilical artery P a o 2 measurements should be supplemented by a measure of the preductal P a o 2 , using either a right radial artery catheter or a transcutaneous monitor placed on the right upper chest. Preductal (right hand) and postductal (either foot) Sp o 2 measurements give useful additional information.
Weaning the baby with persistent pulmonary hypertension of the newborn off therapy
Once the baby has acceptable blood gases weaning can begin. This should be done cautiously as, for some days afterwards, a fall in PAP and a decrease in the right-to-left shunt can result in the pulmonary arteries once more going into spasm, perhaps due to the sensitising effects of alkalaemia ( ). The ventilator pressure should be reduced to <30 cmH 2 O first, and then the rate of infusion of the vasodilator drugs reduced. In PPHN, the ventilator pressures should never be reduced by more than 1–2 cmH 2 O increments and the oxygen concentration by no more than 3–5% increments.
If a pneumothorax occurs, it must be drained; the hypoxaemia caused by a pneumothorax may so aggravate the pulmonary arterial vasocontriction that it pushes the baby into irreversible hypoxaemia, hypotension and bradycardia. PIE is particularly difficult to manage, as a reduction in ventilator pressure will almost inevitably result in a rise in P a co 2 and a reduction in pH and P a o 2 , with worsening of the PPHN. The preterm baby with PPHN who is severely hypoxaemic, acidotic and/or hypotensive is at risk of brain injury, particularly if hypocapnia is used as treatment.
Natural history and prognosis
This varies with the aetiology. Many neonates respond promptly to treatment and the resulting mortality is low, in the 10–20% range, with most of the deaths being due to complications of prematurity or the neurological sequelae of severe birth asphyxia. For those requiring ECMO with primary PPHN or PPHN complicating RDS or MAS, survival figures of 80–90% are reported ( p. 525 ). Most babies die either from irreversible hypoxia secondary to the PPHN or from myocardial failure as bacterial toxins cause arrhythmias or profound hypotension. The results in diaphragmatic hernia are given in Chapter 27, part 6 .
Whether or not sequelae occur in survivors depends on whether the intensity of respiratory support caused BPD and whether any neurological damage resulted from severe hypoxia.
Meconium aspiration syndrome
MAS results from the inhalation of meconium before, during or immediately after delivery.
In Europe the incidence is between 1 : 1000 and 1 : 5000, whereas in North America rates of 2–5 : 1000 have been reported. In Australia and New Zealand, the rate of MAS was 0.43 : 1000, with a decrease in incidence between 1995 and 2002 ( ). Five per cent of babies born through meconium-stained liquor develop MAS ( ).
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 ):
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.
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.
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 ( ).
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 ( ).
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 ( ; ; ).
Effect on pulmonary vasculature
A rise in PAP occurs in all babies with hypoxia and acidaemia ( p. 455 ). Meconium in the lung increases PAP, even if the blood gases are normal ( ). The inflammatory response (see above) results in release of vasoactive substances, which cause vasoconstriction; in addition, there may be maldevelopment of the pulmonary vessels secondary to chronic hypoxia ( p. 450 ).
Petechial haemorrhages may be present on the lung surfaces due to acute hypoxaemia, particularly if death has occurred rapidly after birth. The lungs may be greenish yellow in colour and the cut surface can show congestion and haemorrhage and meconium can be expressed from the cut ends of the smaller bronchi. The pathognomonic histological feature is the presence of amniotic squames, together with meconium in the terminal airways. Meconium itself appears as a granular eosinophilic material, often containing small yellow meconium bodies. Aspirated material will stimulate a macrophage reaction, but, in the absence of an infective process, acute inflammation with neutrophils is not a feature. In addition to the meconium, hyaline membranes are frequently present. There may also be non-specific changes of an asphyxial insult to the lung, which include interstitial oedema and haemorrhage. The changes of PPHN may be seen in the pulmonary vascular tree. Infants who die of MAS will have been ventilated at high pressures and thus the histological changes merge into those of BPD. In babies with MAS who die early in the neonatal period, severe asphyxial damage may be seen in other organs, in particular the brain, kidney and myocardium.
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 ( ; ).
Timing and mode of delivery
A prospective study ( ) demonstrated that reduction in postterm delivery was the most important factor in decreasing the incidence of MAS. MAS is frequently reported to be higher in infants born by caesarean section rather than vaginal delivery; caesarean sections are usually performed on infants with fetal distress, a risk factor for MAS, which may explain the association.
Although it is clear that some meconium can be inhaled prelabour, it is assumed that many cases of MAS arise due to inhalation of meconium during the few minutes before birth. In uncontrolled studies, meticulous clearing of the airway at delivery was reported to reduce the incidence of MAS ( ; ; ). The results of several subsequent studies, however, suggested that routine suctioning through the cords or intubation with endotracheal toilet was not justified, as the manoeuvres not only failed to reduce the incidence of MAS but also were associated with increased morbidity ( ; ; ). Randomised trials have now been reported which have addressed whether intrapartum intubation and tracheal suctioning are necessary. No significant differences in the incidence of MAS or in other major outcomes were demonstrated between babies randomised to receive either naso- or oropharyngeal suctioning prior to delivery of the shoulders or no suctioning ( ). Similarly, no significant differences were demonstrated in the incidence of MAS or other respiratory complications between apparently vigorous infants who were randomised to intubation and tracheal suctioning or routine delivery room care ( ). In addition, meta-analysis of the results of four randomised trials which included vigorous term meconium-stained babies ( ) did not demonstrate significant benefit with regard to mortality, MAS or hypoxic–ischaemic encephalopathy (HIE) from routine endotracheal intubation at birth as compared with routine resuscitation, including oropharyngeal suction. The event rates for the outcomes, however, were low, thus making reliable estimates of treatment effect impossible. Nevertheless, on the evidence to date, intubation and suctioning should be restricted to newborns who are depressed ( ) – that is, they have a heart rate of less than 100 beats/min, poor respiratory effort and poor tone. As soon as possible after delivery, affected babies should be handed to the paediatrician, who should gently insert a laryngoscope and carefully clear the upper airway of any meconium-stained material. If no meconium is seen below the cords, it is not worth proceeding ( ). If, however, meconium is seen, direct tracheal suction is indicated. Studies in animal models have demonstrated that inhaled meconium stayed in the trachea and major bronchial divisions for several minutes after the onset of respiration and was, therefore, still in a site from which it could be aspirated ( ).
The indications for resuscitation by IPPV ( Ch. 13.1 ) are not affected by the presence of meconium, other than it is always important to clear as much meconium from the airway as possible before applying positive-pressure ventilation .
Compression of the neonatal thorax
This is no longer recommended, as it seems unlikely to prevent gasping, which has a large diaphragmatic component, and compression of the thorax can stimulate respiratory efforts.
Instilling water or saline into the lower respiratory tract is controversial; an increase in wet lung has been noted following this procedure ( ) and repeated bronchial lavage can do harm. Once on IPPV, tracheal suction with saline lavage, however, resulted in a 35% improvement in airway resistance in one study ( ). Surfactant lavage can be beneficial (see below).
Postnatal gastric aspiration
Many clinicians routinely aspirate the stomach of a baby who has inhaled meconium at delivery, assuming the baby will have also swallowed meconium and gastric aspiration will prevent subsequent meconium inhalation following vomiting or reflux. Routine gastric lavage prior to feeding, however, did not decrease the incidence of MAS in babies born through meconium-stained liquor ( ).
The baby is usually mature, or postmature, with long fingernails and a dry skin which soon starts to flake. The skin, nails and umbilical cord are often stained greenish yellow. The baby is not usually febrile, unless secondarily infected. Peripheral oedema is not a feature, and, if present, suggests either renal damage or iatrogenic fluid overload.
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.
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 ).
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 ).
Apparently faeculent liquor may be due to yellow-green bilious vomiting secondary to upper gastrointestinal tract obstruction ( ). It is important to exclude concurrent illness, especially infection and PPHN.
The respiratory failure and hypoxaemia in babies with MAS are due to stiff lungs, marked ventilation–perfusion imbalance and pulmonary hypertension precipitating extrapulmonary right-to-left shunts. Babies with MAS have a reduced compliance and tidal volume and an increased airways resistance, but the tachypnoea increases the minute volume to twice normal ( ). In the early stages of the disease, when the airways are plugged by meconium, there is a marked ventilation–perfusion abnormality, which lessens as the lungs recover. In those who develop PPHN, the PAP will be higher than the systemic, with right-to-left shunting through the ductus arteriosus and/or the foramen ovale.
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 ).
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 ).
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.
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 ( ).
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.
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 ).
All babies suffering from MAS should have an infection screen as soon as possible after admission to the NICU.
There is a temptation to undermonitor full-term babies with MAS because, despite marked tachypnoea and a very abnormal CXR appearance, they often look surprisingly pink and vigorous. This temptation should be resisted, not only because of the importance of early detection of blood gas abnormalities, electrolyte disturbance or hypotension before secondary effects develop, but also because the baby with MAS has a major risk of sudden deterioration due to a tension pneumothorax.
The aim is to support the baby until alveolar macrophages clear the debris and lung function returns to normal.
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.
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.
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.
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 ( ).
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 ).
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.
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, 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 ( ).
This is a rare complication of MAS, although it may occur in any baby who survives after long-term high-pressure IPPV.
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.
The neurological sequelae in these babies are those of the coexisting HIE ( Ch. 40.4 ).
MAS predisposes to long-term respiratory morbidity ( ; ; ). In a single-centre study ( ), infants with MAS had later neurodevelopmental delay, even if they responded to conventional treatment. At school age, although the majority of neonates who survived MAS were completely asymptomatic, 30–40% had problems with asthma and less than half had completely normal lung function tests ( ; ). Other data ( ) also suggest that meconium aspiration predisposes to increased bronchial hyperreactivity. The lung function abnormalities at follow-up relate to the severity of MAS ( ). At 6–9 years of age, evidence of residual airways disease was seen in patients who had moderate to severe MAS ( ), whereas 12 children who had had mild MAS had normal lung function ( ).
Aspiration of amniotic fluid
Postmortem studies of stillbirths have revealed that amniotic squames can be inhaled by the fetus in utero, presumably as a result of ‘terminal’ gasping activity preceding intrauterine death ( ). The importance of less severe manifestations of this entity, in the absence of meconium staining of the amniotic fluid, is speculative, but there is a postnatal lung disease attributed to the inhalation of non-meconium-stained amniotic squames ( ).
Aspiration of fluid at delivery
Aspiration of blood can result in early-onset respiratory distress and a radiographic appearance of aspiration syndrome ( ). It occurs during birth by caesarean section or a vaginal birth complicated by abruptio placentae. Aspiration of ‘pool’ fluid during a water birth may also cause respiratory distress ( Fig. 27.36 ).
Other aspiration syndromes ( Table 27.8 )
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.
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.
|Gross anatomical defects|
|Palate||Cleft palate, submucous cleft|
|Tongue||Macroglossia, cysts, tumours, lymphangioma, ankyloglossia superior|
|Mandible||Micrognathia, Pierre Robin syndrome|
|Temporomandibular joint||Ankylosis (congenital or infective), hypoplasia|
|Pharynx||Cyst, diverticulum, tumour|
|Oesophagus||Atresia, stenosis, short oesophagus, web, diverticulum, duplication, lung buds, tracheo-oesophageal fistula|
|Delayed maturation||Prematurity, normal variant|
|Cerebral palsy||All types|
|Brain damage||Postasphyxial, postinfection (prenatal or postnatal)|
|Abnormalities of the cranial nerve nuclei and their tracts||Bulbar and suprabulbar palsy|
|Pharyngeal, cricopharyngeal incoordination (idiopathic, secondary to brain damage)|
|Congenital laryngeal stridor|
|Myopathies||Myotonic dystrophy, myasthenia gravis|
|Hypotonia from any cause||Brain damage, Werdnig–Hoffman syndrome|
|Infections||Tetanus, polio, stomatitis, oesophagitis|
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.
Gastro-oesophageal reflux ( Ch. 29.3 )
GOR should be suspected in neonates with apparently inexplicable and recurrent respiratory problems, especially if there is recurrent apnoea unresponsive to theophylline ( ), a history suggesting reflux or recurrent vomiting, or right upper lobe collapse or consolidation on X-ray. The diagnosis should be confirmed by radiological or pH probe demonstration of reflux ( ; ; ).
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.
This may occur following one of the episodes of sucking/swallowing incoordination or reflux described above and is most likely to occur in babies with neurological defects or structural malformations. It may be covert due to reflux, or can follow an episode of massive regurgitation and vomiting, which usually only occurs in ill and convalescent babies of all gestations on the NICU. The baby, often still tube-fed, is found covered in vomit, and is usually cyanosed, apnoeic or gasping, and bradycardic.
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.
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.
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.
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.
The vomiting episode
When the baby is found, the mouth, nose and pharynx should be quickly and effectively sucked out. If the infant has become cyanosed, oxygen should be given by mask. Most babies respond briskly at this stage and no further treatment is required other than the evaluation outlined above. If the baby does not respond promptly, the airway should be cleared using a laryngoscope and inhaled material aspirated under direct vision. This should always be done if the episode is so severe that the baby remains apnoeic or intubation is required for resuscitation.
Sufficient oxygen should be given to keep the P a o 2 in the normal range. If the aspiration has been severe, or it complicates pre-existing lung disease in a small preterm baby, the episode may trigger apnoea or cause such severe pneumonitis that the baby will require IPPV.
If there are copious secretions following inhalation, or if the CXR shows an area of consolidation, then 4-hourly physiotherapy should be given to encourage drainage from the affected region. The baby should also be nursed in the position that optimises drainage from the affected lobe.
In most babies it is wise to stop oral feeds for 24–48 hours after an episode of aspiration/inhalation. In the preterm neonate, recourse to intravenous feeding may be necessary. In the term baby, once the tachypnoea has settled, oral feeding can be restarted unless there is some chronic problem, in which case a period of nasogastric feeds will need to be used.
Until the cultures are negative, it is impossible to be sure that the whole episode was not triggered by infection. As a consequence, broad-spectrum antibiotic cover should be given, usually flucloxacillin and an aminoglycoside ( Ch. 39.2 ). Antibiotics should be continued for at least 5–7 days or until the baby is clinically much improved if there are marked CXR changes or the neonate required IPPV, even if the cultures are negative.
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.
This condition is a form of fulminant lung oedema with leakage of red cells and capillary filtrate into the lungs. It must be differentiated from the common occurrence of a small amount of blood-stained material aspirated from the ETT of a ventilated baby as a result of trauma. Pulmonary haemorrhage occurs most commonly in babies weighing <1500 g, who often have a PDA ( ).
The incidence of pulmonary haemorrhage in infants with a birthweight less than 1500 g, treated with surfactant, was reported to be 11.9% ( ).
Massive pulmonary haemorrhage (MPH) represents the extreme end of the spectrum of pulmonary oedema in the neonate. This has four main causes ( ) ( Table 27.10 ), which all increase fluid leak into the pulmonary interstitium and thus elevate pulmonary lymphatic flow. Although intra-alveolar fluid may appear at an early stage of interstitial oedema ( ), pulmonary oedema usually occurs as lung interstitial fluid rises and fluid leaks into the alveoli because the alveolar epithelium either has been damaged or becomes leaky owing to distension by the interstitial fluid. The first change is a rise in pulmonary capillary pressure; this causes an increase in interstitial fluid, which eventually leaks into the alveoli through holes in the epithelium. Initially these holes are large enough to allow passage of molecules such as albumin, but small enough to retain molecules such as IgG, IgM, and fibrinogen, and the majority of red cells. As the changes become more marked, the holes in the endothelium and epithelium increase in size and larger molecules leak through. In most cases, the amount of blood lost is small and the haematocrit of the lung effluent is less than 10%. MPH can occur following severe birth depression and in infants with hydrops due to rhesus haemolytic disease, left heart failure, congenital heart disease, sepsis, hypothermia, fluid overload, oxygen toxicity and haemostatic failure. Infants who are small for gestational age are more likely to suffer a pulmonary haemorrhage ( ), the association being independent of other factors ( ). In addition, the neonate with severe RDS on IPPV in a high oxygen concentration and heart failure secondary to a large pulmonary blood flow from a PDA may suffer an MPH ( ; ). Meta-analysis of the results of 29 trials ( ) demonstrated an association of MPH with synthetic, but not natural, surfactant use. Rescue surfactant therapy was not demonstrated to have a significant effect on MPH ( ), but prophylactic surfactant increased the risk (RR 3.28; 95% CI 1.5–9.2) ( ). MPH is seen in babies with DIC, albeit rarely, but does not usually occur in babies with thrombocytopenia, haemorrhagic disease of the newborn or haemophilia. Following the marked clinical deterioration with MPH, however, it is not uncommon for secondary DIC to develop ( ).
|INCREASED PULMONARY MICROVASCULAR PRESSURE||REDUCED INTRAVASCULAR ONCOTIC PRESSURE||REDUCED LYMPHATIC DRAINAGE||INCREASED MICROVASCULAR PERMEABILITY|
|Heart failure||Prematurity||Pulmonary interstitial emphysema||Sepsis|
|Transfusions||Fluid overload||Raised central venous pressure||Emboli|
|Intravenous fat||Hypoproteinaemia||Oxygen toxicity|
|Increased pulmonary blood flow||Loss in gut|
|Pulmonary hyperplasia||Loss from kidneys|
The changes present in the lungs are dependent on the stage of the illness reached by the time of death. In deaths before 48 hours of age and in stillbirths, interstitial haemorrhage is common, but in deaths after 48 hours and following surfactant administration ( ), intra-alveolar bleeding dominates the clinical picture. The lungs are solid at postmortem and usually a deep reddish-purple colour; they are gasless and sink in water. Their pressure/volume characteristics will be those of low-compliance, surfactant-less lungs ( p. 457 ). Hyaline membranes will often be present, since MPH frequently complicates primary RDS. As in RDS, there will be necrosis and desquamation of the alveolar lining cells. In cases which come to autopsy more than 48 hours after the haemorrhage, and particularly if the neonate survives for several days on IPPV, usually in a high oxygen concentration and at high pressures, the changes merge into those seen in severe BPD ( p. 555 ).
The two striking clinical features of MPH are a sudden deterioration and usually the simultaneous appearance of copious bloody secretions from the baby’s airway, either up the ETT or from the larynx and mouth in a non-intubated infant. The baby usually is hypotensive, pale and frequently limp and unresponsive, although term babies may occasionally be active and restless secondary to hypoxaemia, and ‘fight’ the ventilator.
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.
Infants are dyspnoeic and cyanotic and auscultation of the chest reveals widespread crepitations with a reduction in air entry.
Small amounts of blood coming up the ETT are usually due to trauma. A few babies may deteriorate clinically without apparent cause for an hour or two before the haemorrhage develops, but once copious blood-stained fluid appears from the airway, the diagnosis is self-evident. The underlying cause, however, should be established, since this will influence subsequent treatment.
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.
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.
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.
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 ).
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.
The blood gases should be meticulously supervised. Clotting studies should be done daily until they normalise. A daily CXR should be performed because of the high ventilator pressures that are frequently required and the potential complications.
Particular attention must be paid to maintaining the BP with blood transfusion, progressing to inotropes as necessary ( Ch. 28 ). The severe acidaemia should be corrected with intravenous base if IPPV and correction of the hypoxia and hypotension do not promptly return the pH and base deficit to an acceptable level. Underlying disorders must be treated. Heart failure due to anaemia in, for example, haemolytic disease should be treated by exchange transfusion with packed cells, aiming for a haemoglobin level of 13–14 g/dl. Asphyxial myocardial damage may need inotrope support (see below), and sepsis should be treated as outlined on Ch. 39.2 .
Control of pulmonary oedema and heart failure
Fluid input should be restricted to 60–80 ml/kg/24 h, particularly if there is a coexisting patent ductus. The BP can be sustained by judicious infusion of blood, but mainly by the use of inotropes.
These babies have left ventricular failure and pulmonary oedema. Furosemide (1 mg/kg) should be given as soon as possible after the haemorrhage and repeated as necessary, to treat fluid overload.
Intermittent positive-pressure ventilation
All babies with MPH should be intubated and ventilated. They usually have severe lung disease, and peak inflating pressures above 30 cmH 2 O may be necessary. For this reason, and since mature babies in particular become very restless, neuromuscular blockade and sedation should be used routinely until the haemorrhage is controlled. During IPPV, a high PEEP (up to 6–7 cmH 2 O) should be employed; in experimental studies this does not reduce the total lung water, but redistributes it back into the interstitial space, improving oxygenation and ventilation–perfusion balance ( ; ).
Paradoxically, although surfactant may precipitate MPH ( p. 459 ), after stabilising the baby on IPPV after the haemorrhage, a single dose of surfactant has been suggested to improve oxygenation ( ).
Patent ductus arteriosus
PDA is common in preterm neonates who develop MPH; use of prophylactic indometacin may reduce both complications ( ). While the baby is critically ill, the use of indometacin or equivalent is contraindicated, but this should be reconsidered 24–48 hours later, once the coagulopathy is controlled and the hypoxia and acid–base disorders corrected.
In the first few hours after the haemorrhage, there may be copious bloody secretions. Suction is required every 10–15 minutes in extreme cases, as there is a significant risk of the secretions clotting and blocking the airway or ETT. Physiotherapy, however, is not of proven value, and, as these neonates are extremely fragile, it should not be used as a routine in the early stages, instead relying on adequate humidification to keep the secretions sufficiently liquid that they can be sucked up the ETT.
The features of DIC are frequently present. Transfusion of platelets, however, is rarely required, but infusions of fresh frozen plasma are indicated and usually successful in promptly correcting the clotting deficiencies. After the first 24–48 hours when the baby has become stable on IPPV, the acid–base disturbances have been corrected and septicaemia (if present) treated, the coagulation problems usually remit and further factor replacement is not usually necessary.
Sepsis is a recognised cause of MPH; thus, antibiotics should be started after taking cultures. If the baby is already receiving antibiotics, it is recommended to broaden the spectrum to cover infection by staphylococci and Pseudomonas species.
These babies are susceptible to all the major complications of respiratory failure. High-pressure ventilation predisposes them to airleaks, and BPD is a common sequela ( ). At the time of their sudden collapse, they are susceptible to neurological damage and GMH/IVH ( Ch. 40.5 ); the occurrence of cerebral bleeds may be doubled in babies who suffer pulmonary haemorrhage ( ). The occurrence of seizures is increased in infants with pulmonary haemorrhage ( ).
For many years this was regarded as a universally fatal condition ( ). In the modern era of intensive care, survival is improved; but affected infants are the sickest and most immature and their mortality rate is of the order of 38% ( ).
Asphyxial lung disease/acute respiratory distress syndrome
Intrapartum asphyxia or severe lung injury may result in severe respiratory distress ARDS.
ARDS results from lung injury from a number of causes, including asphyxia, shock, sepsis, MAS and DIC.
Asphyxia damages pulmonary blood vessels, making them leaky, and this, plus the pulmonary oedema secondary to heart failure occurring as a result of asphyxial damage to the myocardium ( ; ; ), may compromise surfactant function ( p. 459 ). Severe metabolic acidaemia can also depress myocardial contractility, again leading to heart failure, pulmonary oedema and tachypnoea ( ; ). If the leak of protein-rich fluid on to the alveoli becomes large enough, ARDS develops, with epithelial degeneration, surfactant inhibition, interstitital cellular infiltration, pulmonary hypertension and eventually alveolar fibrosis ( ).
Metabolic acidaemia stimulates hyperventilation ( ). In the neonate, the chemoreceptors are sensitive to pH ( ; ); the increase in respiration is more likely to be due to stimulation of peripheral chemoreceptors than medullary centres ( ).
Damage to the central nervous system may stimulate tachypnoea by two mechanisms. Firstly, the neural control of respiration may be damaged, resulting in hyperventilation. This is well recognised in older patients ( ). Neurologically damaged babies may hyperventilate to P a co 2 levels of 2.5–3.0 kPa (19–23 mmHg) in the first few days after birth. Secondly, neurogenic pulmonary oedema may occur following any rise in intracranial pressure (ICP) or brain injury. It is primarily due to an increased pulmonary vascular permeability leading to interstitial pulmonary oedema, hypoxia and tachypnoea ( ; ). The mechanism is probably active in the newborn, and explains, for example, the sudden deterioration in respiratory function following a GMH/IVH, but may also be of importance in babies with HIE or subdural haemorrhage following birth asphyxia.
Asphyxia caused by cord occlusion with blood trapped in the placenta causing fetal anaemia ( ; ) and acute fetal haemorrhage from ruptured vasa praevia or following a large fetomaternal haemorrhage will result in the birth of a baby who is anaemic, shocked and acidotic ( ). Chronic fetal anaemia due to rhesus disease or fetomaternal haemorrhage also produces babies with acidaemia, anaemia and tachypnoea ( ). The lowered buffering capacity of blood with a low haemoglobin will also potentiate the effect of metabolic acidaemia on respiration (see above).
Some babies who suffer intrapartum asphyxia remain tachypnoeic for 24–48 hours after delivery ( ); less commonly, severe lung disease, ARDS ( ), occurs.
Infants with ARDS are severely hypoxaemic. This is primarily a disease of term babies, who, within the first hour or two, usually present with tachypnoea of 100/min or more, rather than with retraction and grunting, although in some babies the clinical picture may be dominated by the neurological sequelae of asphyxia, and apnoea may occur ( ). The baby may be tachycardic and hypotensive with a triple rhythm, or have the systolic murmurs of tricuspid or mitral incompetence ( ; ); if there has been severe myocardial damage, other signs of heart failure, crepitations and hepatomegaly may be found ( ).
This is a diagnosis of exclusion in the neonate who has suffered intrapartum asphyxia. The CXR excludes complications such as pneumothorax and does not show the features of ‘wet lung’ seen in transient tachypnoea. Excluding sepsis, as always, is important, as GBS infection may masquerade as asphyxia ( ).
The blood gases should be measured on an arterial sample; babies with ARDS are severely hypoxaemic. Respiration is stimulated by the metabolic acidaemia (base deficit >20 mmol/l, with a corresponding low pH), damage to the central nervous system or by lung receptors stimulated by pulmonary oedema; the P a co 2 is usually <4 kPa (30 mmHg). Hypoglycaemia is common after asphyxia, as is DIC ( Ch. 30 ); both should be remedied promptly if found.
A CXR is essential and will demonstrate diffuse pulmonary infiltrates. In severe cases there will be a ‘whiteout’ as in severe RDS.
Evidence of myocardial damage should be sought by performing an echocardiograph to assess ventricular function and an ECG should be obtained. The ECG may show changes of ST-segment depression and T-wave inversion if there is severe asphyxia ( ; ) but in lesser degrees of asphyxia there may only be slight flattening of the T-wave ( ). The level of the myocardial isoenzyme of creatine kinase may be raised ( ). If myocardial damage is present, much greater care has to be taken regarding use of bolus infusions.
A UAC is the preferred site for monitoring blood gases and BP. Affected babies are peripherally shut down, making clinical assessment of oxygenation impossible and arterial puncture difficult; frequent samples may be needed until the pH returns to normal.
Surfactant administration can improve oxygenation in ARDS. It is most effective if given early and in larger doses than in RDS ( ). In adults and children with ARDS, prone positioning has been shown to improve oxygenation ( ).
The baby should receive sufficient warmed humidified oxygen to keep the P a o 2 above 8 kPa (60 mmHg). Prolonged high-pressure ventilation similar to that used for neonatal RDS ( pp. 517–519 ) may be necessary ( ). A high level of PEEP should be used to try and restore the FRC to more normal values; this will also increase the MAP level and hence oxygenation. An excessive amount of PEEP, however, will impair gas exchange by causing alveolar overdistension. High-volume strategy HFO can also improve oxygenation ( ), particularly in those patients who had a positive response to PEEP elevation ( p. 521 ). HFJV has also been used with anecdotal success ( ). Inhaled NO has been used in patients with ARDS to improve oxygenation ( ).
Term neonates can recover spontaneously and quickly from pH levels of 7.10–7.15 and base deficits of >15 mmol/l ( ; ; ). For this reason, immediately after delivery, expectant treatment of uncomplicated metabolic acidaemia is justified if the pH is above 7.10, but an arterial gas should be checked 30–60 minutes later to ensure that spontaneous correction is taking place. If the pH is below this value, or the infant has heart failure attributed to acidaemia, then the pH should be corrected to 7.30–7.40 using the standard formula ( Ch. 35.2 ).
Hypotension and heart failure
These are two of the most serious complications of severe asphyxia, as they are associated with secondary ischaemic injury to the central nervous system, myocardium (endocardial ischaemia), kidneys (renal failure) and intestine (NEC). They must, therefore, be corrected urgently. The general approach to hypotension outlined in Chapter 28 should be followed, taking great care with fluid balance if the myocardium is compromised. In general, the fluid intake should initially be restricted to 40 ml/kg/24 h. If heart failure is present, furosemide should be given. IPPV with PEEP helps to control pulmonary oedema.
A haemoglobin <13 g/dl (PCV <40%) is an indication for transfusion in asphyxial lung disease. If there is coexisting myocardial asphyxial injury, the transfusion should be given slowly and carefully with a diuretic. In such a situation, if the haemoglobin level is <8–9 g/dl, the safest way of increasing it is with a single-volume exchange transfusion using packed red blood cells.
The management of this is outlined in detail in Chapter 40, part 4 .
After collecting the appropriate samples to assess if the baby is infected, including a blood culture, broad-spectrum antibiotics, usually penicillin plus an aminoglycoside ( Ch. 39.2 ), should be administered. Aminoglycoside levels must be carefully monitored, as these infants are at risk of renal dysfunction.
The mortality of ARDS is high ( ), particularly in those infants who develop secondary infection or do not respond to elevation of their PEEP level. Airleaks and infection are commonly seen in infants with ARDS.
These are uncommon in the neonatal period. The incidence of primary fetal hydrothorax is estimated at one case per 15 000 pregnancies ( ).
Pleural effusions diagnosed antenatally are frequently associated with chromosomal or congenital abnormalities ( ). Intrauterine (cytomegalovirus, toxoplasmosis, rubella, adenovirus), perinatal (GBS and Staphylococcus ) and postnatal ( Staphylococcus ) infection can all result in pleural effusions. Isolated effusions are usually a chylothorax ( p. 515 ). Approximately 9% of infants with MAS have pleural effusions; rarer associations are TTN, PPHN, heart failure and congenital myotonic dystrophy. Right-sided diaphragmatic hernia can be associated with a hydrothorax, which results from a fluid-filled peritoneal sac in the right side of the chest ( ). An effusion will develop following repair of CDH ( Ch. 29.6 ). Trauma, for example by direct erosion of the inferior vena cava by a TPN catheter into the pleural space, can result in a pleural effusion ( ). A unilateral hydrothorax may also occur if a central venous catheter migrates into the pulmonary vasculature ( ). Pleural effusions are usually part of a generalised oedematous state (hydrops fetalis); an isolated fetal pleural effusion can progress to generalised hydrops.
Infants with large effusions are frequently difficult to resuscitate as, antenatally, the pleural effusion may have prevented normal lung growth. In infants with underlying pulmonary hypoplasia, there will be a reduced pulmonary vascular bed and the babies will have PPHN. On examination, the trachea and mediastinum will be shifted to the contralateral side and the ipsilateral lung will be dull to percussion with absent breath sounds. Small effusions may be asymptomatic and diagnosed incidentally on a chest radiograph.
Antenatally, pleural effusions are detected by ultrasonography and should be suspected in fetuses whose mothers have polyhydramnios ( ). Postnatally, on the CXR there may be a ‘whiteout’ on the affected site ( Figs 27.38 and 27.39 ), but if the pleural effusion is small, it is important to remember that fluid will collect in the most dependent parts of the chest, around the lateral chest wall or the diaphragm ( Figs 27.40 and 27.41 ).
At birth, the presentation of a large effusion is similar to that of CDH ( Ch. 27.6 ), but there are no bowel sounds in the chest. The CXR appearance may be confused with an eventration or atelectasis.
Antenatally, pleural effusions are drained either intermittently by thoracocentesis ( ) or continuously by a thoracoamniotic shunt ( ). Indications for antenatal drainage include the development of hydrops and mediastinal shift with a unilateral effusion. At birth, infants with large pleural effusions require active resuscitation by intubation and positive-pressure ventilation ( ). Thoracocentesis may also be required to achieve effective ventilation and this may also be necessary later in the postnatal period. See Chapter 44 for details of the technique. Aspirated fluid should always be sent for cytology to determine the lymphocyte count, and for biochemical and microbiological analysis. If the effusion is due to infection, the fluid will have a high protein content, with neutrophils present, and organisms may be isolated. The fluid should also be sent for cytological examination; a high lymphocyte count indicates a chylothorax. If a chest tube is used to drain a pleural effusion, it is important to ensure that the tip does not abut the mediastinum, as this increases the risk of phrenic nerve injury ( ).
Antenatally diagnosed pleural effusions, particularly if present prior to 32 weeks of gestation, have a mortality rate as high as 55% ( ). Bilateral fetal pleural effusions are frequently associated with pulmonary hypoplasia. Postnatally, effusions persisting for more than 3 days increase the risk of chronic oxygen dependency ( ).
One in 10 000 deliveries and one in 2000 neonatal intensive care admissions were reported to have a chylothorax ( ).
Chylothorax may occur spontaneously or be associated with lymphoedema due to congenitally abnormal lymph vessels in conditions such as Turner or Noonan syndrome or congenital lymphangiectasia. In the last condition, there is diffuse dilatation of the interlobular and subpleural lymphatics. A congenital abnormality in the lymphatic system at the level of the thoracic duct below or above the fifth thoracic vertebra leads to a right- or left-sided chylothorax ( ). It can be associated with foregut malformations and extralobar sequestration. Rarely, trauma to the thoracic duct at delivery by hyperexpansion of the spinal column in association with increased venous pressure during birth results in a chylothorax, but more commonly it is a complication of certain types of cardiac surgery (repair of coarctation of the aorta or ligation of a PDA) or repair of a congenital posterolateral diaphragmatic hernia ( ). Another iatrogenic cause is superior vena caval (SVC) obstruction in patients who have had venous catheterisation for TPN ( ).
Unusually, chylothoraces result in hydrops, owing to impairment of venous return by cardiac and vena caval compression and/or loss of protein into the pleural space. In 50% of cases, chylothoraces present in the first week with symptoms as described under isolated pleural effusion. Typically, the lesion is right-sided. Chronic chylothorax may be associated with hypovolaemia, hypoalbuminaemia, hyponatraemia and weight loss. Such patients are immunocompromised owing to loss of lymphocytes and humoral antibodies.
In an unfed infant, the fluid obtained at thoracocentesis is clear, yellow and contains large numbers of lymphocytes (20–50 per high-power field). Lipoprotein electrophoresis demonstrates a high triglyceride and a low cholesterol level. Once the infant is milk-fed, the fluid will become chylous, clearing once a medium-chain triglyceride formula is introduced. Chylothorax associated with SVC obstruction should be suspected in infants with swelling of the face, neck and upper extremities; ultrasonography will confirm the presence of fluid in the chest and the position of the catheter tip. Doppler ultrasonography will identify the SVC obstruction.
Chylothoraces may need to be drained antenatally (see above). Postnatally, many cases respond to a single thoracocentesis, as this results in lung expansion tamponading the defect and preventing further pleural fluid formation. If the fluid reaccumulates, drainage is required and the baby should be fed with a milk containing fat only in the form of medium-chain triglycerides. In the gut, long-chain fatty acids pass into the lymph as chylomicrons after being re-esterified to triglycerides, before entering the venous network, whereas medium-chain fatty acids pass directly into the portal venous blood. Pregestemil or Pepti-Junior can be tried, but a semielemental milk may be required and should be continued for at least 2 weeks after the effusion has disappeared ( ; ; ). Rarely, in non-responsive cases, TPN should be used. Pleural abrasion, ligation of the thoracic duct and pleurodesis are possible options for those chylothoraces that fail to respond to medical management ( ; ).
This condition usually resolves, but the mortality rate has been suggested to be as high as 60% for bilateral chylothoraces ( ).
Trauma with damage to the arteries alongside the ribs from misplacement of a chest drain to drain a pneumothorax is the commonest cause of a neonatal haemothorax; it can also occur at thoracic surgery. Rare causes include clotting abnormalities ( ), penetration of the fetal thorax at amniocentesis ( ), spontaneous rupture of a PDA and arteriovenous malformations.
The CXR will demonstrate a ‘whiteout’, and a radioisotope lung scan can identify an underlying arteriovenous fistula.
Resuscitation by urgent transfusion of blood and clotting factors may be required. Surgical intervention should be considered if a large blood vessel has been traumatised.
Management of neonatal respiratory failure
Supplementary oxygen therapy
In mild to moderate respiratory disease, all that is usually required to keep the baby’s P a o 2 at 8–12 kPa (60–90 mmHg) ( Appendix 7 ) is the administration of warmed humidified supplementary oxygen. Additional support by CPAP or IPPV is indicated only if a satisfactory P a o 2 cannot be achieved in 60–80% oxygen in a headbox, or at lower inspired oxygen concentrations if there are other features of respiratory failure. To avoid sudden changes in the inspired oxygen concentration such as when the incubator doors are opened, the oxygen should be given into a Perspex box placed over the baby’s head and shoulders (headbox). The concentration of oxygen administered should be measured by an analyser placed near the baby’s mouth. This form of therapy is frequently sufficient for preterm babies more than 30 weeks of gestational age with RDS, all babies with minimal respiratory disease and most with TTN ( p. 485 ). The occasional mature baby with RDS and most cases of meconium aspiration can also be managed with headbox oxygen, even though they may require concentrations of up to 80% for 72 hours or more, providing they do not develop other signs of respiratory failure.
A system for automated adjustments in the fraction of the inspired oxygen concentration to maintain the oxygen saturation level within the intended range has been shown to reduce hyperoxaemia ( ).
Nasal cannula-administered oxygen
In babies requiring prolonged oxygen therapy for BPD, administration of oxygen by nasal cannula allows the baby to be picked up and cuddled and bottle- or breastfed. It is, however, difficult to assess the concentration of oxygen administered to such babies. Purpose-built double cannulae or an 8 FG feeding catheter cut to length and inserted 2–3 cm into one nostril can be used. Correct fixation of the catheter to the nostril is important to prevent restricting the flow rate, accidental displacement and excessive advancement of the catheter, which has been associated with gastric rupture ( ). A humidifed high-flow nasal cannula (HFNC) is now used in some centres as an alternative to CPAP; usually flow rates of less than 2 l/min are used (see below). The potential reasons for the increased use are ease of administration, perceived improved tolerance and minimal nasal trauma compared with nCPAP ( ).
Oxygen is toxic to tissues because it forms free radicals, such as superoxide (O 2 − ) and hydroxyl (OH − ) ( ). The neonate is exposed to complex physiological and pharmacological stresses from these agents ( ; ). If adults are exposed to even a few hours of pure oxygen, they develop tracheitis and reduced tracheal mucus velocity. After about 16–24 hours, they experience chest discomfort and cough. During the first 24 hours, there is a significant alveolar–capillary leak of protein ( ). Dyspnoea develops after a further 24–48 hours ( ). If pure oxygen exposure is continued for 3–4 days, animals develop a fatal lung disease with oedematous alveolar walls, interstitial haemorrhage, atelectasis ( ) and type II cell hyperplasia ( ). Surfactant is depleted in the early stages of oxygen exposure, with a reduction in both DPPC and PG levels ( ), which continue to fall after the animal is removed from 100% oxygen ( ; ). Another deleterious effect of breathing pure oxygen is that all the nitrogen is washed out of the alveoli; as oxygen is much more rapidly taken up by pulmonary capillary blood than is nitrogen, this predisposes to atelectasis. Pulmonary alveolar macrophage function is significantly reduced in animals by exposure to more than 80% oxygen for at least 3 days ( ).
Exposure of the neonatal lung to a high inspired oxygen concentration in the presence of lung disease also causes damage, probably because the oxygen free radicals interact with lung cell lipids. Neonates, however, seem to be more resistant to pulmonary oxygen toxicity than are adults ( ). This resistance is dependent on the presence in the tissues of antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase. In the term lung, the cells, including type II pneumocytes, are able rapidly to switch on antioxidant enzymes after birth ( ; ), an effect that may be stimulated by epidermal growth factor ( ), but this is less efficient in the preterm lung ( ; ; ). The level of antioxidant enzymes and the resistance of the lung to hyperoxia are increased at term by prenatal maternal and postnatal treatment with dexamethasone ( ; ). In preterm animals, the postnatal increase in enzymes and oxygen resistance may be absent ( ; ). Administration of surfactant protects against oxygen toxicity ( ; ).
Although 100% oxygen clearly damages the lungs, the danger of lower oxygen concentrations to the human neonate is much less clear. In adult humans, oxygen concentrations less than 60% rarely do harm, and exposure to between 50% and 90% resulted in limited damage ( ). In mature rabbits, exposure to 60% oxygen for 3 weeks caused alveolar interstitial oedema, but increased surfactant production ( ). Rats kept in 60% oxygen for 2 weeks had small lungs with parenchymal thickening ( ). Studies in neonatal baboons suggest that exposure to a high oxygen concentration even without IPPV is damaging ( ).
Administration of 100% oxygen to babies is never justified, as, with large shunts, the increase in P a o 2 achieved by increasing from 90% oxygen to 100% oxygen is trivial and is not worth the risks of both oxygen toxicity to the lung and the atelectasis that results from nitrogen washout.
Assisted ventilation in the newborn
Continuous positive airway pressure
CPAP is a positive distending pressure applied continuously. The aim of CPAP is to hold the alveoli and airways open and prevent them collapsing during expiration. The major benefit of CPAP is that it stabilises the ribcage, reducing chest wall distortion during inspiration and consequently increases the efficiency of the diaphragm ( ). It regularises the respiratory rate, which usually falls because of stimulation of the Hering–Breuer reflex, and results in an increase in inspiratory time and tidal volume. There is an increase in the FRC in proportion to the level of applied pressure; some alveoli, however, will be overdistended, resulting in a fall in dynamic compliance ( ). If too small a diameter tube is used to administer the CPAP, the work of breathing may increase as a result of the increased effort required to overcome the resistance of the tube ( ).
Continuous positive airways pressure delivery
CPAP was initially given through an ETT ( ), but, in an attempt to avoid the hazards of intubation, many other devices have been used, including Gregory’s original headbox, face chambers and negative-pressure chambers. These devices have mostly been abandoned. Facemask CPAP has a high complication rate ( ) and thus is not recommended. The mask must be applied firmly to the face to prevent gas leaks and maintain the pressure and this can distort the baby’s face; furthermore, the apparatus holding the mask in place must be strapped tightly around the back of the head, which can distort its shape. In early series, pressure necrosis and even GMH/IVH or cerebellar haemorrhage were reported ( ). It is difficult to use a nasogastric tube with facemask CPAP because this breaks the seal; yet, without the nasogastric tube, the stomach cannot be easily aspirated and gaseous abdominal distension results. The presence of the facemask also makes it difficult to tend to the baby’s mouth and nose. CPAP is now usually delivered to the baby through either a pair of tubes inserted into both nostrils or a single tube into one nostril. An alternative device, described by , applies a jet of gas near to the exit of the curved attachment for the prongs in a way that mimics the actions of an expiratory valve and thus applies CPAP. This device has been widely used in the Scandinavian studies of CPAP in RDS ( ; ). The method of nCPAP delivery used influences outcome. For example, there is a variation in the resistance to flow with the different nCPAP devices; the resistance is lowest in devices with short double prongs. That finding may explain why meta-analysis of the results of two studies demonstrated that short binasal prongs were more effective at preventing reintubation than were single nasal or nasopharyngeal prongs ( ).
CPAP can be delivered using an underwater seal ( ); if the bubbling is vigorous, the baby experiences vibration of the chest at frequencies similar to those experienced during HFOV ( p. 523 ). During ‘bubble’ CPAP, the column of water in the expiratory limb generates CPAP equal to the length of the tube that is immersed under water. In a small randomised trial of infants ready for extubation, gas exchange was maintained despite a significant reduction in minute volume during ‘bubble’ CPAP, suggesting that the chest vibrations may have contributed to gas exchange. In comparison with historical controls, however, ROP (grades I and II) was commoner in infants supported by bubble CPAP ( ). In a crossover trial ( ) of high- versus slow-amplitude bubbling, no differences were found with regard to oxygen saturation or transcutaneous carbon dioxide levels. Variable-flow nCPAP has been reported to be associated with better lung recruitment than with either continuous flow nCPAP via nasal prongs or continuous flow nCPAP via modified nasal cannulae ( ) and the work of breathing was lower with variable flow CPAP ( ). Those beneficial effects may be due to gas entrainment by the high-velocity jet flows; lung overdistension, however, may occur in infants with mild disease if CPAP levels greater than 6 cmH 2 O are used with variable flow CPAP. In one trial ( ), however, bubble CPAP was equally as effective as variable flow CPAP delivered by the Infant Flow Driver and, indeed, the extubation failure rate was significantly lower with bubble CPAP in infants ventilated for less than 14 days ( ).
During bi-level CPAP two alternating levels of CPAP are delivered; the theoretical benefits are that the switching between CPAP levels might recruit unstable alveoli, the delta pressure generates a tidal volume and some of the respiratory work is unloaded. In a small randomised trial, bi-level nCPAP compared with nCPAP was associated with better respiratory outcomes and shorter duration of respiratory support ( ) .
HFNC delivers CPAP, usually at low levels. It is attractive in that trauma to the nose may be reduced by the use of smaller nasal cannulae than are used during CPAP, but there may be desiccation of the nasal mucosa with associated bleeding and airway obstruction if non-humidified HFNC is employed ( ). The current delivery systems may not prevent excessive pressure delivery to the infant’s airway and this may result in lung overexpansion ( ), and the presence of a leak of 30% can reduce the delivered pressures to less than 3 cmH 2 O ( ). Appropriately powered randomised trials with long-term outcomes are required to determine if HFNC with known pressure delivery is more or less efficacious than current methods of delivering continuous positive airways pressure.
Continuous positive airways pressure settings
In relatively mature infants with acute RDS who have not received treatment with surfactant, CPAP pressures of 5–8 cmH 2 O may be required; however, in immature infants in the recovery stage of their illness who have more compliant lungs, levels in excess of 2–3 cmH 2 O may not be tolerated. It is important not to use too high a CPAP level, as this will cause lung overdistension, resulting in impairment of ventilation and carbon dioxide retention. CPAP and F I o 2 levels should be adjusted on the basis of blood gas analyses. If the neonate still has unsatisfactory oxygenation in 50–60% oxygen, he or she should be intubated and ventilated.
Hazards of continuous positive airways pressure
Traumatic injuries to the nose and face from the prong(s) can occur ( ), including distortion of the nose, flaring of the nose, circular distortion and columella nasal necrosis. Although these can be minimised by good nursing technique, they are not completely avoidable. Randomised comparisons have demonstrated similar rates of injury with binasal prongs, nasopharyngeal tube and mask CPAP ( ; ) and the only significant risk factor for nasal trauma was the duration of CPAP ( ). Nasal CPAP support at 24 hours of age was an independent predictive factor for early-onset septicaemia in a prospective study of 462 ELBW infants ( ). In addition, in a case–control study ( ), nasal CPAP was significantly associated with Gram-negative blood stream infections. The increased risk of infection was suggested to be due to trauma to the nares, increasing ports of entry for bacteria ( ). These adverse effects emphasise the importance of remembering that use of nCPAP requires meticulous attention to the airway and frequent suctioning may be necessary. Rigorous training is required for success; the correct size prongs should be used and the neonate’s neck should be properly positioned ( ).
Airleaks do occur in infants supported by CPAP ( ; ). In a non-randomised study ( ), pneumothoraces developed more often in infants supported by nCPAP than in those supported by synchronised intermittent mandatory ventilation (sIMV). In the COIN trial ( ), the incidence of pneumothorax was three times higher in the CPAP arm; there was no excess of severe ICH or PVL, but pneumothoraces with normal cranial ultrasound findings have been associated with increased adverse neurodevelopmental outcome ( ). nCPAP, then, should never be used in units without facilities for both the rapid recognition and drainage of a tension pneumothorax and the subsequent use of IPPV.
When first introduced, CPAP was applied to babies requiring 50–60% oxygen to keep their P a o 2 >8 kPa (60 mmHg). With increased familiarity, the technique was used earlier in babies with RDS, often when they needed no more than 35–40% oxygen to maintain an acceptable P a o 2 . Used in this way, it improved blood gases and seemed to cause more rapid recovery ( ; ; ; ; ). In early randomised controlled trials, however, the benefits of CPAP seemed to be small ( ) and problems were experienced, and the results of prospective trials of CPAP in babies with relatively mild lung disease suggested that treated babies did less well than controls ( ; ).
Early CPAP is now used in many centres in preference to early intubation and IPPV ( ; ; ; ; ). In non-randomised trials, its use has been associated with a reduction in the requirement for mechanical ventilation and in the incidence of BPD. Comparison with a historical control group demonstrated that use of CPAP rather than intubation and ventilation was associated with fewer procedures related to respiratory support and the amount of pain medication was significantly lower ( ). However, in a large randomised (COIN) trial, which included 610 infants born at 25–28 weeks of gestation, although infants randomised to CPAP had a lower risk of death or need for oxygen therapy at 28 days, there was no significant difference in the rates of oxygen dependency at 36 weeks postmaturational age and the pneumothorax rate was significantly greater in the CPAP group ( ). The higher pneumothorax rate might be explained by use of 8 cmH 2 O CPAP and/or the lower use of surfactant in the CPAP group ( ). If early CPAP is used, many centres termporarily intubate the baby so that surfactant can be given ( ), and administer the surfactant early rather than late ( ). The INSURE (intubation–surfactant–treatment–extubation) method is a combination of early surfactant treatment and early extubation on to CPAP ( ). In one study ( ), the INSURE procedure did not induce any perturbation of cerebral oxygen delivery and extraction, but electrical brain activity decreased for a prolonged time. Meta-analysis of six trials demonstrated that the INSURE approach compared with selective surfactant with continued ventilation in infants with RDS was associated with a significant reduction in BPD, need for mechanical ventilation and airleaks ( ). A larger proportion of the infants in the early compared with the selective surfactant group, however, received surfactant and it is well documented that prophylactic/early surfactant versus selective/rescue surfactant once RDS is established reduces the incidences of BPD/death and airleaks and improves survival (see above). Subsequent studies ( ; ) suggest that use of surfactant in the delivery room and selective use of surfactant are as effective as prophylactic surfactant.
In a randomised trial ( ), which included 207 prematurely born infants, early versus rescue nCPAP (i.e. if necessary after arrival on the NICU) was associated with a reduction in BPD. The early nCPAP group, however, additionally received a sustained inflation of 20 cmH 2 O for 10 seconds using a nasopharyngeal tube and T-piece ventilator, whereas bag and mask inflation was used in the other group with inflation pressures of 30–40 cmH 2 O. In a lamb model, six manual inflations of 35–40 ml/kg compared with no bagging resulted in poorer lung function ( ). Thus, it is possible that early nCPAP did not reduce BPD, but rather volutrauma in the delivery suite increased BPD in the other group.
CPAP is frequently used during the recovery stage of RDS to support neonates following extubation from the ventilator ( p. 529 ) ( ). It is also helpful in the management of infants with recurrent apnoeic attacks ( Ch. 27.4 ); nCPAP dilates the upper airway, which may explain its selective beneficial effects on mixed and obstructive apnoea ( ). CPAP may be beneficial in upper airway obstruction due to Pierre Robin syndrome or congenital laryngeal stridor, when nasopharyngeal CPAP may be preferable, with the tip of the nasal cannula passing through the posterior choanae into the upper pharynx ( ). nCPAP has been used effectively and with an acceptable safety margin during transportation of term and preterm neonates ( ).
Nasal-delivered ventilatory modes
Experience of ventilatory modes delivered by nasal prongs is limited and there have been no large randomised trials to determine whether these techniques offer long-term advantages for neonates.
Nasal prong-delivered IPPV (nIPPV) appears to augment the beneficial effects of nCPAP in prematurely born infants with apnoea ( ); but there were case reports of gastrointestinal perforation with this mode of respiratory support. Meta-analysis of three trials highlighted that use of nIPPV is associated with a significant reduction in extubation failure ( ).
Synchronised nIPPV (snIPPV) has generally been delivered by the Infant Star with a synchronised intermittent mandatory ventilation box (StarSync, Infrasonics, San Diego, CA). The StarSync module provides thoracoabdominal synchronisation via the Graesby capsule placed on the abdomen ( ). In a retrospective non-randomised study, involving analysis of data from 471 infants (242 supported by snIPPV), snIPPV was associated with a reduction in BPD in infants with birthweight 500–750 g, but not overall ( ); there was no excess of gastrointestinal problems ( ). In a smaller ( n = 41) randomised study, post surfactant extubation to snIPPV compared with ongoing ventilation was associated with a lower rate of BPD/death, but no other differences in outcomes ( ). Others ( ), however, have reported that nIPPV in stable premature infants resulted in increased BP and discomfort.
HFOV has been delivered by nasal prongs in case series only ( ; ). One series resulted in a reduction in carbon dioxide levels in some infants with a moderate respiratory acidosis on nCPAP ( ). In another, carbon dioxide levels were lower and pH was higher after 2 hours of nasal HFOV compared with CPAP support in preterm infants older than 7 days ( ).
Continuous negative expanding pressure
This is an alternative way of providing distending pressure in which the infant’s body is placed in a negative-pressure box from which the head protrudes and continuous negative external pressure (CNEP) in the range –4 to –10 cmH 2 O is applied ( ). In patients already ventilated, the peak and PEEPs are reduced by the level of negative pressure applied. Early attempts at CNEP were poorly tolerated, particularly in ELBW infants, because of difficulties in securing the infant and hypothermia. These problems have been overcome by specially designed neck seals ( ) and providing a circulation of warm air. CNEP can, however, overdistend the lung and impair lung function in infants with BPD. The considerable technical challenges have meant that CNEP is not widely used in the UK.
Early studies ( ) demonstrated that CNEP was associated with improvements in oxygenation; the best results were experienced in infants with severe RDS. In addition, respiratory rate decreased and, in infants with stiff lungs, compliance improved on CNEP ( ). In a randomised trial ( ), use of CNEP (–4 to –6 cmH 2 O) was associated with a lower duration of oxygen therapy (18.3 versus 33.6 days), but there were trends towards an increase in mortality and cranial ultrasound abnormalities in the CNEP group. Follow-up at school age demonstrated no important differences in respiratory outcomes for those who had been treated with CNEP as infants, but the trial was not powered to detect such differences ( ).
Intermittent positive-pressure ventilation
There are two absolute indications for starting IPPV:
sudden collapse with apnoea, bradycardia and failure to establish satisfactory ventilation after a short period of bag and mask ventilation
failure to establish adequate spontaneous ventilation in the labour ward after prompt and active resuscitation ( Ch. 13.1 ).
The relative indications for intubation and IPPV apply to babies who are breathing spontaneously, but are clinically, or on the basis of blood gas results, showing signs of impending respiratory failure. These indications vary with the gestational age of the baby, the nature of the underlying disease and whether the major feature of the respiratory failure is carbon dioxide retention, hypoxaemia or recurrent apnoeic spells.
Most babies in impending respiratory failure fall into one of three clearly separate groups, which require different plans of action:
VLBW neonates <28 weeks of gestation and <1.00 kg. These babies may be ventilated from the time of resuscitation in the labour ward ( Ch. 13.1 ). A small number of these infants establish adequate regular respiration after birth but subsequently develop signs of RDS. To prevent sudden collapse with its attendant complications and to give surfactant, such babies should be ventilated once they need more than 40% oxygen on CPAP to keep their P a o 2 <7–8 kPa (52–60 mmHg) or have a P a co 2 >6–6.5 kPa (45–50 mmHg) with a pH <7.25.
Babies 1.00–1.50 kg at 28–32 weeks of gestation with RDS. Nasal CPAP may be sufficient support for infants whose P a co 2 is 6.5–7.0 kPa (50–55 mmHg) but who maintain their pH >7.25 and have an oxygen requirement of less than 60%. If, however, CPAP does not result in a prompt improvement, that is, a reduction in supplementary oxygen requirement to less than 40%, such babies should be ventilated.
Relatively mature babies 1.50–2.50 kg and 33–36 weeks’ gestation. These babies have a more rigid ribcage and better developed respiratory muscles than very immature babies, so are more able to sustain vigorous respiratory efforts and tachypnoea for some days. They may, however, tolerate CPAP badly, becoming distressed and irritable when the device is attached.
Other indications for IPPV in the neonatal period include:
PPHN: for the neonate with primary PPHN or secondary pulmonary hypertension, intubation and control of the P a co 2 within defined limits can be beneficial ( p. 498 )
severe early-onset sepsis ( Ch. 39.2 )
diaphragmatic hernia: these babies should be ventilated from birth ( Ch. 27.6 )
HIE: hyperventilation to prevent cerebral oedema by keeping the P a co 2 in the 3.0–3.5 kPa (22–25 mmHg) range ( Ch. 40.4 ) is no longer justified, but sedation due to anticonvulsant drug administration often necessitates intubation and ventilation
apnoea: the small preterm baby with recurrent apnoeas, not controlled by methylxanthines or CPAP, requires IPPV ( Ch. 27.4 ).
A continuous flow of gas is delivered and this distends the lung for a preset inflation time to a predetermined pressure. During expiration, the ventilator gas flow continues to deliver PEEP if required. Gas enters the lungs during the inspiratory time; the amount entering is determined by the set peak pressure and the gas flow rate. The latter should always be large enough to ensure that the preset peak pressure can be reached during the available inflation time. At a fast flow, the lungs are distended more quickly and the peak pressure is reached sooner, thereby creating a relatively square-wave inspiratory gas flow. When the desired pressure has been reached, the pressure-limiting valve opens and prevents any further rise. The longer the inflation time, the longer the lungs are held distended at this pressure. The higher the pressure is set, depending on the compliance of the lungs, the larger the volume of gas which enters the lungs, though this is limited in non-compliant lungs by the size of the leak around the ETT.
Peak inflating pressures.
When starting a baby on IPPV, the peak inflating pressure should be adjusted to ensure adequate, but not excessive, chest wall expansion; in practice this usually equates to a delivered volume of approximately 6 ml/kg ( ). Sufficient pressure must be used to achieve acceptable blood gases. Since high pressures/volumes are likely to cause a pneumothorax ( p. 487 ) or lead to BPD ( p. 552 ), the lowest possible peak pressure compatible with normal blood gases should be employed. In general, the starting pressures for a baby with respiratory distress should be about 16–18 cmH 2 O. The peak pressure is then adjusted according to the blood gas results, which should be determined within 15 minutes of commencing mechanical ventilation. Underventilation produces a high P a co 2 and a low P a o 2 , and overventilation a low P a co 2 and sometimes an excessively high P a o 2 .
This acts like CPAP to hold the peripheral airways open during expiration. PEEP should always be used during ventilation, as it conserves surfactant on the alveolar surface, except in severe PIE or certain cases of overinflation ( ). If too high a PEEP level is applied, particularly if combined with a short expiratory time, the lung cannot deflate properly. This causes hyperinflation, a reduced tidal volume and compromised gas exchange, and the P a co 2 rises accompanied by a fall in P a o 2 . Early studies demonstrated that a PEEP of about 5 cmH 2 O, rather than no PEEP or much higher levels, improved oxygenation ( ; ); the mechanism was via the effects of MAP on lung volume and oxygenation. The results of subsequent studies suggested that babies with acute RDS or apnoea do not require more than 3 cmH 2 O of PEEP ( ; ). Babies who have severe RDS which does not respond to surfactant can require higher PEEP levels to optimise lung volume ( ). Infants ventilated beyond the first week without cystic chronic lung disease have improved oxygenation at 6 cmH 2 O ( ).
Mean airway pressure.
There is a good correlation between the MAP level and oxygenation ( ; ), such that P a o 2 may be improved by increasing the inspiratory time, the level of PEEP or the peak inflating pressure, all three manoeuvres elevating MAP. Elevation of the PEEP level, however, is the most effective method of increasing lung volume and hence oxygenation. At a critical level, determined by the infant’s lung function, further elevation of the MAP level can impair oxygenation. The MAP level can be calculated from various formulae, but they assume a square-wave inflating pressure and therefore overestimate the MAP. Such calculations are now rarely necessary as the MAP level is displayed on most currently available ventilators.
Historically, babies with RDS were ventilated at a ventilator rate that matched their respiratory rate, about 80–100/min, but this resulted in a high incidence of BPD ( ). Studies ( ; ; ) then showed that if an I : E ratio of 1 : 2 was used, the P a o 2 was higher at ventilator rates of 30/min compared with 80/min. At a rate of 30/min, the P a o 2 was found to be higher if the inspiratory time was longer than the expiratory time (a reverse I : E ratio) and 5 cmH 2 O of PEEP was employed. Those data were restricted to neonates with severe RDS. Nevertheless, by the late 1970s, ventilator rates of 20–40/min with long inspiratory times were being widely used in infants with all types of lung disease, with an incidence of pneumothorax and other forms of airleak of 35–40% ( p. 486 ). Subsequently, faster rates were preferred. found that they could ventilate babies at 60/min with inspiratory times of 0.5 seconds at lower peak inspiratory pressures and with better blood gases and fewer pneumothoraces than when rates of 30/min and inspiratory times of 1 second were used. Subsequently, it was demonstrated ( ) that, when babies with RDS were kept at the same MAP, rates of 120/min produced an improvement in P a o 2 compared with rates of 30 and 60/min; the improvement resulted from the neonates breathing in synchrony with the ventilator. By increasing the ventilator rate as necessary up to 100/min, most neonates were induced to breathe in synchrony ( ; ) and thus had better blood gases ( ), but whether synchrony decreased the pneumothorax rate was not investigated. Meta-analysis of randomised trials ( ) has demonstrated that high-frequency positive-pressure ventilation compared with conventional mechanical ventilation (CMV) significantly reduced the incidence of airleaks. No advantages of rates in excess of 20–40/min have been demonstrated in infants born at term and in paralysed infants; it is important in such infants to keep the ventilator rate at 60/min or less to reduce the likelihood of gas trapping ( ).
Inspiratory and expiratory times, I : E ratios.
In the 1970s, I : E ratios of 2 : 1 or even 3 : 1 were applied, giving inspiratory times as long as 1.5 seconds. This increased the MAP and improved oxygenation, but the reverse I : E ratio, with a concomitant prolongation of the inflation time, was one of the factors that correlated with the high pneumothorax rate ( ; ). Subsequently, the average inspiratory and expiratory times in ventilated babies with RDS were demonstrated to be 0.31 seconds ( sd 0.06 seconds) and 0.42 seconds ( sd 0.13 seconds), respectively ( ), i.e. an I : E ratio of approximately 1 : 1.3. Employing such a ratio with an appropriate rate for gestational age ( ) resulted in many babies with RDS breathing in synchrony with the ventilator, with an attendant improvement in oxygenation. Similar studies have not been undertaken in very immature infants with mild lung disease who have received both antenatal steroids and postnatal surfactant therapy; but it is likely that such infants, if they have vigorous respiratory efforts, would be best ventilated with a physiological I : E ratio (i.e. a longer expiratory to inspiratory time) and a rate similar to their spontaneous respiratory frequency. An I : E ratio of 1 : 1 results in best gas exchange for babies ventilated beyond the first week after birth ( ).
Ventilator settings with pressure-limited ventilators ( Table 27.11 )
Babies with abnormal lungs
Initially guided by the baby’s colour and chest expansion, the following initial ventilator settings are appropriate, providing the chest wall moves adequately, until the result of blood gas analyses is available ( Table 27.12 ):
Pressure: 18–20/3 cmH 2 O
Inspiratory time: 0.3–0.4 seconds
Oxygen concentration: 60–80%