Neonatal respiratory physiology

This chapter is not relevant to any specific Section from the 2023 CICM Primary Syllabus, because there is no specific entry for neonatal respiratory physiology in the Respiratory section. However, in the Important to note section of the syllabus, the examiners mention that trainees are expected to have " an understanding of normal physiology,  and physiology at the extremes of age, obesity, pregnancy (including foetal)...". The "including foetal" presumably extends to the neonatal range of ages, which is from 0 to 30 days by convention. This had become the topic of Question 6 from the first paper of 2020 and Question 7 from the first paper of 2013. Each time, the college wanted us to compare the neonatal respiratory system to that of the adult.

Most of the differences are anatomical, and so no attempt will be made to separate structure from function. Instead, the best classification would probably be one which focuses on broad domains of difference, describes each difference and explains its relevance.

Davis & Mychaliska (2013) cover this subject to a depth which will please all but the most demanding reader. Unfortunately, Elsevier have their article under lock and key. Similarly, Neumann et al (2014) is excellent but paywalled by Wiley. The dumpster-diving freegan will have make do with LoMauro & Aliverti (2016), which is unfortunately (or fortunately?) a lot less detailed. 

Airway differences

The unique challenges of the neonatal and paediatric airway are already listed elsewhere. Here, in a brief summary to remind the reader, the main differences are:

• Small mandible
• Large tongue
• Larger tonsils and adenoids
• Superior laryngeal position
• Soft, narrow, short trachea

The functional implication of these changes, as a completely separate issue to the problem of intubating the neonate, is the softness and floppiness of these structures. With very negative or very positive intrathoracic pressure, the soft airways will not resist collapse, and stridor may ensue.

Airway resistance

• Respiratory resistance is increased at birth. The main reason for this is the presence of residual fluid in the lung. As one might recall, lung volume is a major influence on airway resistance, and at birth the lungs are collapsed. Ergo, resistance is high until all the amniotic fluid is expelled.
• Lower airway resistance is generally increased in infancy, mainly because the bronchi are smaller (as the whole organism is smaller), and because resistance is related to the fourth power of the radius, it is increased. 
• The lower airways are also more compliant, which gives rise to dynamic collapse during forceful inspiration. 

Anatomy, volumes and spirometry

Though it is not referenced and comes from 

• The ribs are horizontal and the diaphragm is flattened. This places all the respiratory muscles into positions of mechanical disadvantage. 
• FRC is similar to the adult FRC, although it would be lower if the neonates did not employ various FRC-increasing manoeuvres (like autoPEEPing, as discussed below).
• Tidal volume is unchanged.  Adult VT and neonatal VT are both around 6ml/kg at rest. However, in the neonate, the anatomical and physiological dead space is increased, which means more of their tidal volume is wasted. 
• Minute volume is increased, mainly because of the increased respiratory rate. The normal healthy neonate will breathe comfortably at a rate of around 40. There are several reasons for why this is necessary:
  • There is more anatomical and physiological dead space
  • The tidal volume is limited by the increased chest wall compliance (i.e. with higher respiratory effort it will collapse - see below)
  • The tidal volume is limited by decreased lung compliance due to the lack of surfactant
• Lung volumes are markedly different: these data come from god knows where, but the numbers appear legitimate and resemble those published in the Nurse Anaesthesia E-Book by Nagelhout et al (2010, the 4th ed):

  Respiratory Volumes in the Adult and Neonate

  Volume	Adult volume (ml/kg)	Neonate volume (ml/kg)
  Tidal volume	6	6
  Total lung capacity	86	63
  FRC	34	30
  Vital capacity	70	35
  Residual volume	16	23
  Closing capacity	23	35

  
  In the form of a diagram, it looks like this:
  
   
• RV is larger than in the adult, ERV is small, and FRC is very close to RV. The main reason for this is the increased chest wall compliance, i.e. the soft floppy chest wall is insufficiently rigid to maintain a large intrathoracic volume at the end of tidal expiration, and tends to collapse to a lower volume. Various "expiratory braking" techniques are employed by the neonate to increase intrathoracic expiratory pressure and defend this volume (see below).
• Closing capacity is increased. Mansell et al (1972) found that of all age groups, teens had the lowest closing volume, and it was highest in neonates and the elderly. From the high neonatal value, it takes a long time to mature, and only decreases to equal the FRC at about the sixths year of life.
• Pores of Kohn are immature. These collateral communications between alveoli do not form until closer to the end of the first year of life.
• Large physiological dead space is usually mentioned by textbooks. Appparently, most of this is due to an increase in anatomical dead space.  Numa & Newth (1996) report that it starts at around 3.0 ml/kg of body weight in neonates, whereas among adults it is closer to 2.2 ml/kg. 
• Large alveolar dead space is occasionally reported. Most studies which report large values,  eg. 0.96 ml/kg from Wenzel et al (1999) are guilty of using mechanically ventilated neonates, and so their findings may not be reflective of normal human babies. For the normal adult, alveolar dead space is expected to be zero. 

Lung and chest wall compliance

• Lung compliance is decreased. The main reason for this is an insufficiency of surfactant. Apparently, it takes some days to synthesise an appropriately large amount of it. Moreover, at birth, the lungs are full of fluid, and relatively large pressure swing (∼30 cmH₂O) is required in the first few breaths of life, which only produces about 40 mL of tidal volume. The neonate autoPEEPs up to a positive pressure of 35 cm H₂O with a closed epiglottis, and sustains this pressure for up to 30 seconds to recruit those waterlogged alveoli (Pas et al, 2008).
• Lung compliance is difficult to compare to adults.  In order to compare adults and neonates, one has to use specific compliance (i.e. indexed to volume), otherwise the neonates would seem to have preposterously low lung compliance. The specific compliance is usually indexed to FRC, which in the neonate remains roughly proportional to the adult FRC (as a fraction of TLC). 
• Chest wall compliance is increased.  At birth, the chest wall is three times more compliant than the lungs, and it takes the whole first year of life for them to achieve something closer to adult values. The main reason for this is the cartilaginousness (cartilaginicity?) of the neonatal ribs. They are made of cartilage, is what I am trying to say.  In fact the chest wall is so compliant that it may not be sufficiently rigid during deep inspiration. This sets a functional limit to the maximum tidal volume possible, when the respiratory effort is increased. Trying to inhale a larger tidal volume requires a greater negative intrathoracic pressure, which causes the soft neonatal chest wall to collapse, which decreases the tidal volume.  The upshot of this is the greater reliance on the respiratory rate in order to increase minute volume.
• The compliant chest wall does not defend the FRC very well. As already mentioned, if it were not for various reflexive mechanisms which maintain a positive end-expiratory pressure, the FRC of the neonate would be lower.

Gas exchange and oxygen-carrying capacity

• Increased shunt is sometimes described in textbooks, which - they say - is 10% at birth; however there is often no reference for this value. Looking for its origins, one usually comes across studies which report a far larger value, mainly because at birth the ductus arteriosus is still patent, and up to 25% of pulmonary blood flow is diverted into the systemic circulation. Nelson et al (1962) reported that at least a quarter of the cardiac output was shunted in normal calm neonates, with the fraction increasing to two-thirds when they were distressed.
• Increased total oxygen-carrying capacity of the blood is usually seen, which is largely the effect of increased haemoglobin and haematocrit. The neonate usually rocks a Hb of 190g/L or above, which gives a potential 250ml of oxygen per litre of blood at 100% saturation. 
• Foetal haemoglobin produces a left-shift of the oxygen-haemoglobin dissociation curve, which increases the binding of oxygen but decreases its release to the tissues. This increased affinity takes about 4-6 months to return to normal values, as foetal haemoglobin is replaced with normal adult haemoglobin.
• A post-natal increase in 2,3-DPG rapidly reverses this left shift and decreases the affinity of foetal haemoglobin for oxygen in the first 2-3 days of life (Davis & Mychaliska, 2013).
• Pharmacodynamics of oxygen includes different toxicities as compared to adults; specifically the neonates are prone to retinopathy and bronchopulmonary dysplasia when they are exposed to high oxygen concentrations. 

Control of ventilation

• Expiratory braking:  the breathing pattern shortly after delivery is designed to maximise alveolar recruitment.  The first breaths have a short inspiratory time and a prolonged expiratory time, with a sustained period of high positive airway pressure (Kosch et al, 1988).  By a reflexive mechanism, the diaphragm contracts following inspiration to delay the passive recoil of the lungs and chest wall, and the glottis adducts in order to resist outward airflow. 
• The central respiratory control mechanisms are immature. Rigatto (1984) summarises the resulting peculiarities very well. In short: 
  • Ventilatory response to CO₂  is blunted in magnitude, i.e. the increase in the minute volume is lower than what would normally be expected in the adult
  • Ventilatory response to CO₂ is reversed in the presence of hypoxia (i.e. the highest ventilatory response is seen at the high O₂ concentrations, which is the opposite of what happens in adults).
  • In the presence of hypoxia, neonates decrease their minute volume, again the opposite of what happens in adults.
  • Brainstem respiratory rhythmogenesis is immature: neonates may have a slowly oscillating respiratory rate and intermittent apnoeas

Work of breathing and respiratory demand

• The total oxygen consumption of the neonate is increased. A figure of around 6-10ml/kg is usually quoted in the textbooks; Davis & Mychaliska (2013) report an increase of 100-150% from what is seen during neonatal life.  This reflects an increased metabolic rate, and is in turn associated with increased CO₂ production. Therefore the overall demand on the respiratory system is increased. Add to this the poor lung compliance and the floppy chest wall, and you will conclude that the work of breathing for the neonate must surely be increased.
• Work of breathing is increased.  Because of all the abovementioned changes in resistance and compliance, it takes more effort to produce breaths, and the more (and deeper) breaths, the more the effort.  Therefore there is a point of compromise where the tidal volume is low enough and the respiratory rate is high enough that maximum efficiency is achieved. OpenAnaesthesia give a legitimate-sounding value of 37 breaths per minute, which appears to come from Cook et al (1957); though it appears that there is a broad range of respiratory rates over which the respiratory efficiency does not change overmuch (between 30 and 50 breaths per minute).
• The diaphragm is more susceptible to fatigue. At birth, the diaphragm has fewer Type 1 muscle fibres (the slow endurance type of muscle fibres which increase the fatigue resistance of muscle). Thus, the diaphragm of neonates and preterm infants is susceptible to fatigue after prolonged "sprints". This has implications for respiratory failure and the weaning from mechanical ventilation.

Pathologies are potentially also worth mentioning, purely because some of them differ significantly from the phenotypes of respiratory failure which the adult intensivist would be the most familiar with.  From the viewpoint of somebody accustomed to large old humans,  the most alien neonatal respiratory problem would probably have to be bronchopulmonary dysplasia. The typical neonatal respiratory distress syndrome starts acutely like ARDS with poorly compliant lungs, where the immediate problem is surfactant-deficiency and therefore derecruitment. It then progresses into an unfamiliar chronic phase, characterised by a slow recovery and managed completely differently to adult ARDS. It seems to exist only where evolved nonatal ICU exists, because it only affects those infants who survive their initial period of respiratory failure. As Northway Jr et al (1967) put it, "intensive therapy may modify the acute syndrome so as to permit the development of a previously unrecorded abnormality of the lung"

The definition for a formal diagnosis of BPD is ongoing oxygen requirement or respiratory support needs at 36 weeks postmenstrual age, whereas the same dependence in the weeks prior is called "evolving BPD". "Dependence" and "respiratory support" are probably too imprecise for this readership; for more clarity, Jensen et al (2019) defines three grades, where Grade 3 is ventilator-dependent at 36 weeks and has a mortality of 81%. Considering that 40% of pre-term infants develop some degree of BPD, that sounds serious.

The cause of this persistent problem is a failure of the normal development of alveolar architecture and pulmonary vasculature, but it is harder to characterise it more clearly.  Higgins et al (2018), trying to make sense of the theories, complained that the history of this disorder since it was described (in 1967) spans several periods of major upheaval in critical care practice which have shifted the blame for it from ventilator-induced lung injury and VAP to other aetiologies. These days the infants getting BPD are smaller, more pre-term, and systemically sicker than they were in the 1960s, and so the pathology seen today is likely different to what was described by Nortway et al.  The current view is still to regard this as failed lung construction. The main problem seems to be a disturbance of the saccular and alveolar stages of lung development where secondary septatation and micorvascular maturation occur. Without wading too deep into the deep cold waters of embryology, it will suffice to say that the lung is, fundamentally, a balloon animal, formed by the initial extension and branching of long hollow tubes that create elongated saccules initially (at around the 24th week of gestational age), and then become separated into alveoli when their air spaces become divided by septa. It is not exactly clear what compells the lungs to do this in this exact point of human development, but the presence of high oxidative stress (i.e. high FiO₂) barotrauma and inflammatory cytokines seems to interrupt it. Logically, the result is a smaller gas exchange surface, with simplified alveoli and abnormal pulmonary microcirculation (Thekkeveedu et al, 2017; Thebaud et al, 2019; Hysinger & Ahlfeld, 2023).

The main reason to go on this digression is that textbook recommendations for the management for the chronic phase of this disease are cardinally different to what is usually seen for adult ARDS.  some authors recommend slower rates, longer inspiratory and expiratory times, higher PEEP, and large tidal volumes that would look deranged in adult ARDS (Miller et al, 2022; Ozkan et al, 2022). The authors argue that the small airways disease that accompanies the fibrotic chronic changes results in lung units which are capable of contributing to gas exchange but which have very slow time constants; and the prolonged expiratory time allows more time for passive CO₂ clearance. Conversely small tidal volumes are observed to increase respiratory distress, and on that basis, larger ones are better. Others, hilariously, retort that references used to support this strategy come from book chapters that either reference each other or cite supporting papers that do not contain anything supportive. After several scathing pages dismantling the high volume-slow rate method, this more recent publication recommends sticking with conventional adult-like lung protective strategies.