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Received: 12 November 2021    Revised: 2 December 2021    Accepted: 5 December 2021

DOI: 10.1111/pan.14362

E D U C AT I O N A L R E V I E W

Developmental respiratory physiology

Daniel Trachsel1  | Thomas O. Erb2  | Jürg Hammer1 |

Britta S. von Ungern-­Sternberg3,4,5

1
Pediatric Intensive Care and Pulmonology,
University Children’s Hospital of Basel Abstract
UKBB, Basel, Switzerland
Various developmental aspects of respiratory physiology put infants and young chil-
2
Department Anesthesiology, University
Children’s Hospital of Basel UKBB, Basel,
dren at an increased risk of respiratory failure, which is associated with a higher rate of
Switzerland critical incidents during anesthesia. The immaturity of control of breathing in infants
3
Department of Anaesthesia and Pain is reflected by prolonged central apneas and periodic breathing, and an increased risk
Management, Perth Children’s Hospital,
Perth, WA, Australia of apneas after anesthesia. The physiology of the pediatric upper and lower airways
4
Division of Emergency Medicine, is characterized by a higher flow resistance and airway collapsibility. The increased
Anaesthesia and Pain Medicine, Medical
chest wall compliance and reduced gas exchange surface of the lungs reduce the pul-
School, The University of Western
Australia, Perth, WA, Australia monary oxygen reserve vis-­à-­vis a higher metabolic oxygen demand, which causes
5
Perioperative Medicine Team, Telethon more rapid oxygen desaturation when ventilation is compromised. This review de-
Kids Institute, Perth, WA, Australia
scribes the various developmental aspects of respiratory physiology and summarizes
Correspondence anesthetic implications.
Daniel Trachsel, Pediatric Intensive Care
and Pulmonology, University Children’s
KEYWORDS
Hospital of Basel UKBB, Spitalstrasse 33,
Postal Box, CH -­4031 Basel, Switzerland. airway, physiology, growth, child, control of breathing, airway obstruction, compliance
Email: [email protected]

Section Editor: Thomas Engelhardt

1  |  I NTRO D U C TI O N odds ratio of critical incidents in infants less than a year by a factor
of four compared to older children. 2
Significant differences in respiratory physiology between infants Following the path of a breathing cycle, pulmonary gas exchange
and adults explain the higher vulnerability of the infant respira- requires.
tory system for decompensation and failure. In general, breathing
efficiency is determined by the work of breathing per tidal breath -­ a functional neural control which includes the initiation and
and the gas exchange achieved per tidal breath. Numerous factors coordination of the breathing cycle, the maintenance of upper
render the infants’ respiratory system less efficient (Table 1), and a airway patency, and the generation of protective reflexes
variety of counteractive mechanisms exist to compensate for the re- -­ building-­up of a pressure gradient to generate an airflow and to
spiratory instability. However, anesthesia and/or severe illness may overcome the airway resistance, the viscoelastic forces, and the
compromise these counteractive mechanisms or they may prove inertia of the lungs and the chest wall
counter-­productive (eg, laryngospasm). Respiratory adverse events -­ bronchiolo-­alveolar gas mixing and diffusion of gas across the air-­
are common in pediatric anesthesia and comprise more than three blood barrier
quarters of all critical incidents and half of all unplanned admissions -­ renewal of oxygenated and decarbonized capillary blood.
to the pediatric intensive care unit, and approximately a third of car-
diac arrests during anesthesia is attributed to respiratory complica- All four functions are negatively affected by developmental
1
tions. Unsurprisingly, young age is a major risk factor, increasing the characteristics.

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© 2021 The Authors. Pediatric Anesthesia published by John Wiley & Sons Ltd.

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108    
wileyonlinelibrary.com/journal/pan Pediatric Anesthesia. 2022;32:108–117.
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TA B L E 1  Aspects of developmental respiratory physiology

In summary, three distinct properties characterize the vulnera-
contributing to respiratory vulnerability of infants (adapted from
ref.65) bility of the newborn's ventilatory responses: (1) a hypoxic ventila-
tory depression which quickly reverts the initial hypoxic ventilatory
stimulus to a level of ventilation below the normoxic level,8 (2) a
Cause Physiological and anatomic basis
slower response rate to hypercapnia in preterm born babies,9 and (3)
↑ Metabolism O2 consumption ↑
a virtual absence of the potentiating, “more-­than-­additional” effect
↑ Risk of apnea Immaturity of control of breathing of concomitant hypercarbia on the hypoxic ventilatory response,
↑ Upper airway resistance Preferential nose breathing which develops only during the first two months of life.10 Hypoxic
Airway diameter ↓ ventilatory depression persists up to 6 months postnatally.11 A key
Airway collapsibility ↑ point is that the arousal and ventilatory response to hypoxemia or

Pharyngeal muscle tone ↓ airway obstruction is heterogenous and hardly predictable for the
individual infant.12
Compliance of upper airway
structures ↑ Furthermore, breathing stability is influenced by the immaturity

↑ Lower airway resistance Airway diameter ↓ of respiratory cycling and the protective reflexes. Immature breath-
ing control manifests as apneas, either as a single event or in series
Airway collapsibility ↑
as periodic breathing. Both events are primarily considered a physio-
Elastic recoil ↓
logical phenomenon awaiting stabilization with evolving maturation.
↓ Lung volume Number of alveoli ↓
Concerns of possible associations with sudden infant deaths have so
Lack of collateral ventilation
far remained unproven.13
Rib cage compliance ↑
Differentiating normal apnea from a pathological respiratory
↑ Work of breathing Metabolism ↑ pause remains a clinical challenge. Typical physiological apneas
Airway resistance ↑ result from the irregular breathing pattern in rapid eye movement
Defense of FRC (REM) sleep or follow deep sighs or movements, likely with the aim
Respiratory rate ↑ of opposing slow lung de-­recruitment and maintaining functional
↓ Efficiency of respiratory Efficiency of diaphragm ↓ residual capacity (FRC), respectively. According to the American
muscles Horizontal insertion of the Association of Sleep Medicine (AASM) manual, central apneas are
diaphragm at the rib cage scored if lasting ≥20 s or being accompanied by an arousal, a ≥3%
Efficiency of intercostal muscles ↓ oxygen desaturation, and/or a bradycardia.14
Horizontal ribs Frequency and duration of central apneas during sleep decrease

↓ Endurance of respiratory Fatigue-­resistant type I muscle over the first 12 months of life. Typical central apneas in neonates
muscles fibers ↓ last 3–­6  s,15 but apnea durations of 20 s or more are not uncom-
mon in healthy subjects <4 weeks of corrected gestational age.13 In
older infants, longer apneas are still seen in infants referred for ob-
2  |  D E V E LO PM E NTA L A S PEC T S O F served apneas,16 but apneas lasting more than 15–­20 s become rare
B R E ATH I N G CO NTRO L in unselected healthy infants,17 while the 95th frequency percentile
of shorter pauses ≥3  s remains at 15  events/hour at 12  months.18
2.1  |  Respiratory drive Healthy school-­aged children and adolescents show an average of
1–­2 apneas/hour of ≥10  s duration, most of which, however, are
Breathing activity starts with sporadic diaphragmatic movements below the 20 s threshold of the AASM scoring rule.19
toward the end of the first trimester and gains stability during gesta- Periodic breathing in infancy is considered a distinct phenome-
tion, but remains unstable in utero, with breathing activity occurring non of immaturity of breathing control, reflecting altered chemore-
30% to 60% of the time at term. Fetal breathing is important for fetal ceptor reactivity and loop gains to changing pO2 or pCO2 levels, thus
lung growth,3 and breathing activity is already influenced in utero allowing larger breathing fluctuations. 20 The incidence of periodic
by the partial pressures of CO2 and O2 (pCO2 and pO2)—­increasing breathing diminishes toward term, from 83% of cases at 37 weeks of
pCO2 and energy supply stimulate fetal breathing while hypoxia de- corrected gestational age (in infants prematurely born at 34 weeks of
4
presses diaphragmatic activity. gestation) to 41% at term in newborn babies one week after birth. 21
At term, chemoreceptor pCO2 sensitivity and its characteristics The reduction of periodic breathing, however, seems to depend on
are almost mature, but minute ventilation at any pCO2 is higher in the respiratory stability during the preterm phase. Studies suggest
neonates and infants compared with adults.5 This is in contrast to that large pO2 fluctuations typically seen in unstable preterm babies
prematurely born infants who show an attenuated sensitivity to increase hypoxic chemoreceptor reactivity of the carotid bodies.
increasing pCO2.6 In contrast, peripheral pO2 receptors require re-­ The increased loop gain favors intermittent hyperventilation leading
adjustment to the higher oxygen levels ex utero, gaining sensitivity to hypocapnia and consequent apneas and periodic breathing, 22 in-
7
during the first days of life. terestingly a breathing pattern which continues to be a physiological
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110      TRACHSEL et al.

feature of breathing during sleep at high altitude. 23 Hypoxemia thus 2.3  |  Anesthetic considerations about
increases the time spent in periodic breathing, 24
while increasing developmental physiology of breathing control
pCO2 reduces periodic breathing in infants. 25
Control of breathing is prone to perioperative disturbances in all
patients undergoing anesthesia, independent of the applied anes-
2.2  |  Protective reflexes thetic technique (Table 2). Among children, young infants are more
frequently affected by clinically relevant disturbances.35 Prevention
Laryngeal and respiratory reflex responses (eg, laryngospasm, glot- and handling of postoperative apnea in former preterm infants is a
tic spasm/closure, expiration reflex, apnea, spasmodic panting, and matter of continuous debate.36,37 Of note, a large variability in the
cough reflex) represent important defensive strategies securing the incidence of apneas is reported rendering firm conclusions and
integrity of lower airways from aspiration of foreign bodies. 26 There recommendations for the individual patient difficult. Nonetheless,
is a lack of comprehensive scientific information regarding develop- identified individual risk factors for an association with postopera-
mental aspects of these reflex responses in humans. However, ex- tive apnea include decreasing gestational age at birth, anemia, a his-
perimental research in animals provides convincing evidence about tory of recent apnea, ever receiving methylxanthine, ever receiving
the existence of developmental characteristics of these reflexes; for mechanical ventilation, and ever needing oxygen support.36,38 The
example, a discrete period of transient hyperexcitability was iden- GAS study demonstrated a lower incidence of early apnea requiring
tified in pups 50–­75 days postnatally resulting in an increased risk less interventions in the regional (spinal) anesthesia compared to the
of laryngospasm. Suggested mechanisms include central synaptic general anesthesia group.38 However, the same study showed no
maturation, changes in central latency, and transient reduction of difference between the odds of late apneas in the first 12 h postop-
central inhibition resulting in an imbalance of excitatory and inhibi- eratively between infants allocated to a spinal anesthetic or a gen-
tory brainstem influences. 27 eral anesthetic, which has implications for postoperative monitoring
It is important to distinguish between a coughing reflex and an of these children. Interestingly, a brief anesthetic or sedation period
expiration reflex. While a cough is a combination of an inspiration in the patients with regional anesthesia in the GAS trial did not in-
and a forceful expiration, expiration reflexes do not include an in- crease the overall incidence of observed apneas; 6.1% of preterm
spiration. Particularly in combination with glottic closure, expiration infants presented with apnea compared to only 0.3% of term infants
26
reflexes can lead to severe hypoxic episodes. (OR 21.9).38 Furthermore, anesthesiologists have to keep in mind
Protective reflexes also influence spontaneous breathing in the that early apneas are strong predictors of late apneic episodes, but
very young. Particularly in preterm babies, the pressure of a face they are nonetheless not a sensitive measure. During the preopera-
mask may induce bradycardia and apneas by stimulating stretch re- tive planning, the relatively high failure rate of regional anesthesia of
28
ceptors of the trigeminal nerve, known as trigemino-­cardiac reflex. around 10% has to be considered.39
This reflex is at the base of the diving reflex which is stimulated upon
submersion into (cold) water and accompanied by laryngeal closure,
and it is conceived as a powerful protective oxygen-­preserving re- 3  |  D E V E LO PM E NTA L PH YS I O LO G Y O F
flex increasing survival in hypoxic conditions. 29
The most powerful TH E A I RWAYS
stimulus of the trigemino-­cardiac reflex is a sudden mechanical tis-
sue stretch, and predisposing risk factors in the anesthetic setting The infantile supraglottic airway is small and soft, and fundamental
are young age, light anesthesia, and hypoxia and hypercapnia. 29 physical laws act together to make it vulnerable for inspiratory col-
Placing a face mask in infants commonly elicits a transient change lapse. Laplace's Law implies that for any given surface tension the
in breathing pattern consisting of an augmented tidal volume and transmural pressure and thus the collapsing forces increase propor-
reduced respiratory rate.30 tionally to the reduction of the airway radius, and Bernoulli's Law
The Hering-­
Breuer reflex represents a pulmonary volume-­ states that airflow streaming through a narrowing increases flow ve-
31
feedback loop affecting inspiratory muscle activity. Lung disten- locity and decreases pressure within the narrowing. Airway patency
sion not only reduces or even abolishes inspiratory muscle activity is thus dependent of the transmural pressures of parapharyngeal tis-
but also prolongs the respiratory cycle and hence the time of passive sue and the distending pressures within the airways.40 According to
32
expiration. This is referred to as the Hering-­Breuer inflation reflex. the Starling resistor model, the critical closing pressure of the phar-
Its primary physiologic function is thought to be the prevention of ynx during quiet unimpeded inspiration is smaller both than the up-
both overdistension at high lung volumes and de-­recruitment at low stream, atmospheric pressure and the downstream pressure within
lung volumes, as shortening of the expiration at lower lung volumes the large airways.41 Once the critical pressure of the parapharyngeal
32
reduces the risk of de-­recruitment and atelectasis. This might ex- tissue supersedes the downstream pressure, snoring occurs, and a
33
plain why it is more active in the neonates and young infants. The further increase to above the atmospheric pressure results in com-
reciprocal aspect of the lung volume-­feedback loop is the Hering-­ plete obstruction. To counteract this inherent vulnerability, infants
Breuer deflation reflex which delineates the increased inspiratory show an enhanced genioglossal electromyographic activity con-
effort upon rapid lung deflation.34 sequent to increasing inspiratory loading.42 Immaturity, sleep, and
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TA B L E 2  Potential implications of the developmental respiratory physiology for anesthesia in infants and toddlers

Physiological characteristics Consequences for anesthesia in infants and toddlers

Immaturity of breathing control and reflex control Consider risk of apnea postoperatively up to 12 h postintervention in newborns and
premature infants (up to 60 postconceptional weeks)
Expect apnea and bradycardia from forceful face mask application in preterm born
babies (TCR)
Expect hypoxic respiratory depression and bradycardia
Expect transiently increased risk of laryngospasm in preschool children
Small anatomical dimensions of the laryngeal and Increased risk for potential airway damage
tracheal airway Age-­and size-­appropriate selection of laryngeal mask airways and endotracheal tubes
Increased vulnerability for postextubation upper airway obstruction
Increased upper airway collapsibility and resistance Expect airway occlusion from improper head positioning or inexpert execution of
airway opening maneuvers during anesthesia
Expect more rapid gastric inflation
Increased risk for anesthetic complications during upper respiratory tract infections
Higher chest wall compliance Expect rapid lung de-­recruitment and atelectasis with anesthesia, particularly with
neuromuscular blockade
Use of PEEP and assisted ventilation early after induction
Decreased number of alveoli and lack of collateral Decreased respiratory reserve and increased risk for atelectasis
ventilation Consider using low FiO2 (≤ 0.8 during induction) to prevent absorption atelectasis
formation and pulmonary shunt
Increased lower airway collapsibility and resistance Increased risk for anesthetic complications during lower respiratory tract infections
Increased risk for airway collapse during agitation
Expect less effect of inhaled bronchodilators particularly in infants
Higher metabolism Expect more rapid oxygen desaturation with alveolar hypoventilation
Expect more rapid hypercapnia due to increased CO2 production

sickness reduce these counteractive mechanisms, which is associ- competing interests of minimizing work of breathing and anatomical
43
ated with a marked reduction in minute ventilation. Obstructive dead space.50
apneas occur as a physiological phenomenon in normal young in- Airway smooth muscle contractility and reactivity to acetylcho-
fants with up to 3 obstructive events/hour being reported in the line increase with age, 51 and airway smooth muscle tension stiffens
first 3 months of life,16,44 and central apneas in newborns frequently the immature trachea.52 Although airway smooth muscle tone is a
end with short pharyngeal obstructions.45,46 In addition, spontane- determinant of airway caliber, data suggesting that the bronchial
ous neck flexion may induce obstructive apneas in preterm babies.47 patency in infancy actually depends on airway smooth muscle tone
It has to be kept in mind that the adenoids continuously increase in are not convincing and should in our opinion be eliminated from the
size in the preschool and early primary school age before starting to textbooks. While early reports did suggest that short-­acting bron-
regress toward adolescence, highlighting the higher risk of mechani- chodilators reduce maximum airflow at FRC by forced expiration ma-
cal obstruction in this age group.48 neuvers in some wheezy infants, 53 the findings were not replicated
While the parapharyngeal walls depend on tissue interdepen- in healthy infants.54 In addition, transient reduction of oxygenation
40,49
dence, muscle tone, and body position to keep the airspace open, after short-­acting beta-­agonist treatment in severely wheezy infants
airways from the larynx down to the small bronchi are additionally rather reflects worsening ventilation-­perfusion matching in clinical
stabilized by a cartilaginous scaffold. The basic construction princi- practice,55 and paradoxical deterioration of lung function to short-­
ple of the lower airways resembles the fractal tree of Mandelbrot acting beta-­agonists does not occur more often in children with
with dichotomous division of each airway for 20–­23 generations, tracheobronchomalacia.56
the airway diameter being reduced by each division by a factor of The lower airways show a growth spurt during the first 3 years,
about 0.8.50 This design implies that all gas exchange units are sit- becoming less compliant with age.57 The infant's tracheal length is
uated at approximately the same distance from the central airways, already at about 40% of its adult size, but only at 10%–­15% of its
irrespective of the distance from the pleura, and that the cumulative cross-­sectional area.57 The tracheal and bronchial diameter cor-
cross-­sectional area of all the bronchi increases from one generation relates best with age, while the airway length correlates better
to the next, thus decreasing the total airway resistance toward the with body length. Airway parameters correlate poorly, in contrast,
periphery.50 It appears that this stepwise airway diameter reduc- to body weight.58 The cartilaginous scaffold lengthens and stiffens
tion by a factor of about 0.8 is the optimal trade-­off between the with maturation during childhood. While new airway cartilages are
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112      TRACHSEL et al.

formed until the 25th week of gestation only,59 progressive reduc-

tion in water and proteoglycan content render the airway cartilages
increasingly stiffer with age.60 This is reflected, for example, by
the common functional improvement of congenital laryngomalacia
during the first months in affected infants.61 Importantly, cartilage
growth and maturation are influenced by excessive intrinsic or ex-
trinsic pressure application, causing localized or long-­stretch airway
malacia.62 Children with bronchopulmonary dysplasia and a history
of positive pressure ventilation, for instance, are at risk of developing
trachea-­bronchomalacia. This results in an increased work of breath-
ing and a higher risk of recurrent hospitalization during infancy, but
usually resolves in the first 2–­3 years of live.63 In addition, prolonged
positive pressure ventilation in very immature children has been as-
sociated with larger airway diameters and mild tracheomegaly.64
The connective tissue network of the surrounding lung paren-
chyma is crucial to maintain small airways open, especially the ter-
minal and respiratory bronchioli which lack cartilages (Figure 1, from
ref.65).66 Due to this pulmonary interdependence, the airway dimen-
sions change within limits proportionally to cube root of the changes
in lung volume. That is, the airway diameter of airways sized >2 mm
increases proportionally with lung inflation until the transpulmo-
nary pressure has reached approximately –­5 to –­7  cmH2O, which
is about half the intrapleural pressure reached during normal tidal
breathing, that is, at the end of a normal inspiration.67 Pulmonary de-­
recruitment (below FRC) thus significantly affects airway resistance
F I G U R E 1  Model of pulmonary interdependence and elastic
Raw, which is inversely proportional to the 4th power of the airway recoil forces infants and adults (from ref.,65 copyright Elsevier, with
radius with laminar flow. To account for this dependence of lung in- permission)
flation, Raw is commonly indicated as specific resistance at FRC, that
is, Raw/FRC. Importantly, as lower lung volumes reduce the resistive During anesthesia in children, upper airway obstruction is a fre-
load against which the constricting airway smooth muscle work, lung quently encountered problem,70 and failure to maintain the airway
inflation has also a direct impact on the degree of bronchoconstric- open may rapidly result in hypoxemia, bradycardia, or cardiac ar-
tion following airway smooth muscle activation.68 In other words, rest.70 Anesthesia-­related narrowing of the upper airways is most
there is an inverse relation between the strength of the elastic re- likely to appear in pharyngeal structures.71 In particular, obstruction
coil of the connective tissue and the severity of bronchoconstriction is caused by a posterior displacement of the hyoid bone which re-
upon airway smooth muscle activation. duces airway dimension mainly during inspiration when the rims of
Due to the collapsibility of human airways and the pulmonary in- the epiglottis approach the posterior pharyngeal wall.72
terdependence, increasing the pleural pressure with forced expiration Young children are particularly susceptible to upper airway ob-
leads to dynamic airway compression and, eventually, airflow limita- struction not only because of the smaller dimensions of their air-
tion. The importance of the elastic recoil forces to airway patency is ways but also due to the physiological tonsillar and/or adenoidal
exemplified by the significant bronchial obstruction seen in adult pa- hypertrophy.73 A substantial number of children, especially those
tients with severe emphysema. Similarly, the fewer alveoli and intersti- undergoing ear-­nose-­throat surgery, present with a clinically signif-
tial septa of immature lungs offer considerably less suspension forces, icant narrowing of their upper airways, which may manifest as ob-
such that forced expiration and coughing readily lead to peripheral structive sleep apneas (OSA). MRI studies show that children with
airway collapse in babies.69 During early childhood, continued alve- OSA have a significantly smaller volume of their upper airway along
olarization by the formation of new alveolar septa increases the fine with significantly larger adenoids and tonsils compared to patients
interstitial network suspending collapsible airways (Figure 1). without OSA.74 Additionally, in children with OSA, the soft palate
is thickened and consequently contributes to the restriction of the
upper airway.74
3.1  |  Anesthetic considerations about Airway occlusion due to improper head-­neck position during re-
developmental physiology of the airways suscitation potentially contributes to increased neonatal mortality.
Various head positioning and airway maneuvers are described to main-
In children, establishing and maintaining airway patency is a corner- tain airway patency during anesthesia and resuscitation in children. In
stone of safe anesthesia and also a key feature during resuscitation. neonates, an MRI-­based examination revealed that the probability of a
TRACHSEL et al. |
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patent airway progressively increases with increasing head-­tilt angle.75 and thus an improved ventilatory efficiency during exercise, as a
Nonetheless, there is a large overlap of specific positions, making crit- higher proportion of each tidal breath reaches the gas exchanging
ical assessment of the clinical condition necessary.75 A comparison of area VA . A further decrease of the VD/VA ratio during the first years
preschool vs. school children showed that the optimal head-­tilt po- of life results from a relative decrease of the extrathoracic anatomic
sition for airway patency differed between the two groups; while in dead space from 2.3 ml/kg to 0.8 ml/kg, while the intrathoracic dead
younger children a neutral position proved to be the ideal condition, a space is independent from age at approximately 1 ml/kg.83 During
49
head extension of about 15° was superior in school children. quiet breathing, however, dead space related to tidal volume (VD/V T )
In sedated, spontaneously breathing children aged 2–­12 years, remains age-­independent at roughly 33%.84
lateral positioning increases cross-­sectional area and total upper Dysanaptic growth is discussed as a pathological process when
72
airway volume compared with supine positioning. Here, the area airway growth seems to exceedingly lag behind lung growth. This is
between the tip of the epiglottis and the vocal cords demonstrates commonly assumed if flow parameters by pulmonary function test-
the greatest relative percent increase in size. However, simple head ing are disproportionally low compared to the lung volume in the
rotation may already elicit a significant increase in the ante-­posterior absence of active bronchoconstriction, for example, by a lower than
distance and hence the cross-­sectional area in the retroglossal re- normal FEV1/VC ratio, particularly in the presence of a normal FEV1.
gion, along with a volumetric increase of the upper airway.76 It has been discussed in the context of asthma and obesity,85 lung
Simple methods to maintain airway patency include airway ma- growth after pneumonectomy,86 and in prematurity and broncho-
neuvers such as chin lift, jaw thrust, or the use of continuous positive pulmonary dysplasia,87 and it may be hypothesized after congenital
airway pressure (CPAP). Jaw thrust is the most effective maneuver to diaphragmatic hernia repair, after resection of congenital lung anom-
open an obstructed airway and improve ventilation in anesthetized and alies and with long-­standing tobacco exposure. It implies that hypo-
unconscious patients, irrespective of the age of the patient.77 While plastic conducting airways have limited capacity of catch-­up growth.
chin lift is effective in healthy children without tonsillar hypertrophy, The main implication of pathological lung dysanapsis is the potential
it has, however, the potential to obstruct the airway in children with impact on lung function decline with aging and the development of
hypertrophic tonsils and adenoids when the mouth is closed. CPAP chronic obstructive pulmonary disease (COPD).88
with or without jaw thrust and chin lift can further improve upper air- Alveolarization is associated with a re-­arrangement of alveolar cap-
way patency in sedated or anesthetized children, but may decrease illaries, enhanced surfactant production, and a thinning of the alveolar
ventilation in some patients.77 The effectiveness of oro-­pharyngeal, septa with a reduction of the interstitial lung tissue.89 During the first
naso-­pharyngeal, and laryngeal mask airways depends on the correct years of live, this thinning of the alveolar walls allows the formation
positioning of the devices in the pharynx. Due to the large and age-­ of pores of Kohn and later on the pores of Lambert,90 inter-­alveolar
78
dependent variability of the palatal and oro-­pharyngeal morphology, and bronchiolo-­alveolar shortcuts that enable collateral ventilation,
the design of these devices, for example, the radius of the curvature or and thus aeration of ventilatory units distal to obstructed conduct-
the length of the distal portion of oro-­pharyngeal airways, determines ing airways. During the early stage of alveolarization, the capillary
the effectiveness in the individual patient. Landmark rules, formulas, network within the alveolar septa is arranged in a double layer, and
or nomograms thus may help choosing the appropriate size but need thinning of the alveolar septa in the mature lung is accompanied by
validation in the clinical setting. a re-­arrangement of the capillaries into a single layer.89 Although this
facilitates gas transfer into the blood, resting diffusing capacity of the
lung correlates to and linearly increases with lung volume, and is not
4  |  D E V E LO PM E NTA L PH YS I O LO G Y O F different in neonates than in adults,91 that is, the gas exchange sur-
TH E LU N G PA R E N C H Y M A face of a healthy newborn already provides the same weight-­adjusted
oxygen-­uptake capacity at rest as the lung of an adult.
Alveolarization is the formation of new alveoli, a developmental pro- A significant determinant of diffusing capacity is the ventilation/
cess that starts in the beginning of the 3rd trimester and continues perfusion (V/Q) matching. While in adults, ventilation and perfusion
postnatally. While earlier morphometric studies suggested contin- are mainly directed into the dependent lung areas by gravity,92 ven-
ued alveolarization until the age of 2–­3 and 7–­8 years, respectively, tilation in children is more often directed toward the nondependent
newer techniques suggested ongoing formation of new alveoli into part of the lungs, or variable during breathing.93 V/Q matching is
79–­81
adolescence, to a final count of 270–­790 million. The size of the thus weaker in children than adults.
alveoli is estimated to roughly double during growth and be inde-
pendent of body size.81 The primary goal of alveolarization is the
enlargement of the gas exchange area from <10 m2 to about 80–­ 5  |  D E V E LO PM E NTA L PH YS I O LO G Y O F
130 m2 in an average adult.50 TH E C H E S T WA LL A N D D I A PH R AG M A N D
The term dysanaptic growth refers to the disproportionately IT S I NTE R AC TI O N W ITH LU N G
larger absolute growth of the lung parenchyma relative to the growth
of the conducting airways.82 It is primarily a physiologic phenomenon Lung growth follows the growth of the thoracic cage, which is de-
that leads to a lower dead space-­to-­alveolar volume ratio (VD/VA) termined by elongation of the spine and expansion of the chest. The
 |
114      TRACHSEL et al.

thoracic spine lengthens by 50% during the first 5 years and ends at lead to small airway closure, atelectasis, ventilation-­perfusion mis-
94
approximately 2.5 times the length at birth. Simultaneously, the match, and eventually hypoxemia.103 This is even more pronounced
chest volume grows from an original 6% of its final volume at birth with the use of neuromuscular blockade.104 In fact, the majority of
to 30% at 5 years and 50% of the final thoracic space at 10 years of children under 3 years of age, particularly when using neuromus-
age, respectively.94 Severe thoracic restriction obviously is associ- cular blockade, develop atelectases immediately after induction of
ated with smaller lungs, but whether chest expansion surgery which general anesthesia.105 Both the application of PEEP and recruitment
increases the thoracic volume by radiographic volumetry and thus maneuvers may reverse atelectasis and restore FRC and ventilation
the space available for lungs just leads to lung tissue expansion or also homogeneity.106
95
stimulates growth and alveolarization remains debated. Volatile anesthetics reduce respiratory muscle activity and tone,
The two important changes in chest physiology occurring during starting with the glossopharyngeal muscles, involving then the in-
the early years of life are the stiffening of the chest wall and the tercostal muscles and finally the diaphragm.107 Thus, an increased
sternal downshift of the more horizontally positioned ribs of the in- resistance of the upper airway is followed by thoraco-­abdominal
fant into a slanting position in the older child.96 Activation of the asynchrony, presenting with an inspiratory inward movement of the
auxiliary respiratory muscles leads to effective thoracic breathing in ribcage and a simultaneous abdominal expansion.107 Except from
the older individual by elevating the ribs into a horizontal position, desflurane, volatile anesthetic agents reduce FRC, particularly in
which increases the thoracic volume both in the anterior-­posterior young children with highly compliant chest walls. Conversely, des-
dimension (pump-­handle movement of the ribs) and in the lateral di- flurane may lead to bronchoconstriction in children with hyperre-
95
mension (bucket-­handle movement). Infants less than 12 months active airways.108
97
are more dependent of diaphragmatic breathing, and the inter- Propofol leads to a dose-­dependent reduction of FRC and in-
costal muscles are pivotal in stabilizing the chest during inspiration creasing ventilation inhomogeneity in spontaneously breathing
as evidenced by the paradoxical breathing in severe spinal muscle preschool children.109 Midazolam, when used as a premedication in
atrophy. preschool children, may cause a small reduction of FRC and respi-
The interaction of chest wall stiffness and lung compliance is a ratory compliance as well as an minor increase ventilation inhomo-
major component of developmental respiratory physiology, and it is geneities.110 In addition, benzodiazepine-­induced muscle relaxation
reflected by age dependency of the volume-­pressure curve of the increases upper airway resistance, which may further compromise
respiratory system. In the first year of life, the chest wall is nearly breathing.111 Ketamine is unique among hypnotic drugs with regard
98
three times as compliant as the lung. With the progressive stiff- to its effects on respiration, as increasing doses have little impact on
ening of the chest wall during the first year of life the lung volume-­ FRC and ventilation homogeneity, whereas the effect on breathing
adjusted compliance of the respiratory system slightly decreases.99 frequency is variable, ranging from apnea to an increased respira-
Toward the end of the second year, the chest wall compliance has tory rate.112 Opioids may activate chest and abdominal wall muscles,
98
decreased to nearly equal the lung's compliance. From this time-­ potentially leading to chest wall rigidity in adults.103 In children, the
point on, the lung's elastic inward recoil and the chest wall's outward phenomenon is less well described, and difficult mask ventilation
movement stay in balance at a site on the pressure-­volume curve, may be caused by active upper airway obstruction after sufentanyl
where breathing efficiency is at an optimum. In addition, it is at the in some children.113
nadir of the U-­shaped pulmonary vascular resistance curve that in- During anesthesia, high inspired fractions of oxygen (FiO2) are
creases both toward lower and higher lung volumes. used at induction of anesthesia or during the treatment of adverse
During infancy, the compliant chest wall offers less resistance events in order to increase the oxygen reserve and maintain oxy-
to the lung's inward recoil. Hence, the relaxation volume of infants genation. However, a high FiO2 leads to lung de-­recruitment, ven-
is reduced and estimated at only 10%–­15% of total lung capacity, as tilation in homogeneities, and ventilation/perfusion mismatch.114
opposed to 30%–­35% in adults.100 As this moves the lungs toward FiO2 >80% during the induction and emergence of anesthesia
or below the closing volume,69 that is, the volume at which atelecta- leads to decreased lung volumes in the immediate postoperative
sis ensues, the infant actively defends its FRC, mainly by sustained period and persistent ventilation inhomogeneity, which normal-
tonic diaphragmatic activity during the entire respiratory cycle.101 izes 24 h later.115 Recruitment maneuvers can be successfully used
102
This is associated with an increased work of breathing. to reverse this effect. Recruitment maneuvers and atelectasis in
pediatric anesthesia are discussed in detail in another article of
this special issue.116
5.1  |  Anesthetic considerations about
developmental physiology of the lungs and the
chest wall 6  |  R E FLEC TI V E QU E S TI O N S

As infants and young children are dependent of their active FRC 1. How does immature breathing control manifest in newborns?
defense, anesthesia and deep sedation, which counteract the lung 2. How do central apneas change over the first 12 months of life?
volume-­preserving strategy, cause a reduction of FRC which may 3. Describe potential developmental aspects of laryngospasm.
TRACHSEL et al. |
      115

15. Stein IM, White A, Kennedy JL Jr, Merisalo RL, Chernoff H, Gould
4. How does airway configuration change when bringing children in JB. Apnea recordings of healthy infants at 40, 44, and 52 weeks
lateral positioning? postconception. Pediatrics. 1979;63:724-­730.
5. What are the physiologic consequences of dysanaptic lung 16. Sanchez I, Vega-­Briceno L, Munoz C, et al. Polysomnographic find-
ings in 320 infants evaluated for apneic events. Pediatr Pulmonol.
growth?
2006;41:215-­221.
17. Kelly DH, Riordan L, Smith MJ. Apnea and periodic breathing in
AC K N OW L E D G E M E N T S healthy full-­term infants, 12–­18 months of age. Pediatr Pulmonol.
Open Access Funding provided by Universitat Basel. 1992;13:169-­171.
18. Schlüter BBD, Trowitzsch E. Polysomnographic reference curves
for the first and second year of life. Somnologie. 2001;5:3-­16.
DATA AVA I L A B I L I T Y S TAT E M E N T
19. Verhulst SL, Schrauwen N, Haentjens D, Van Gaal L, De Backer
Data sharing is not applicable to this article as no new data were cre- WA, Desager KN. Reference values for sleep-­related respiratory
ated or analyzed in this study. variables in asymptomatic European children and adolescents.
Pediatr Pulmonol. 2007;42:159-­167.
20. Khoo MC, Kronauer RE, Strohl KP, Slutsky AS. Factors inducing
ORCID
periodic breathing in humans: a general model. J Appl Physiol.
Daniel Trachsel  https://orcid.org/0000-0001-8971-9473 1982;53:644-­659.
Thomas O. Erb  https://orcid.org/0000-0001-9263-2352 21. Oliveira AJ, Nunes ML, Fojo-­Olmos A, Reis FM, da Costa JC.
Britta S. von Ungern-­Sternberg  https://orcid. Clinical correlates of periodic breathing in neonatal polysomnog-
raphy. Clin Neurophysiol. 2004;115:2247-­2251.
org/0000-0002-8043-8541
22. MacFarlane PM, Ribeiro AP, Martin RJ. Carotid chemorecep-
tor development and neonatal apnea. Respir Physiol Neurobiol.
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