Seminars in Pediatric Surgery 22 (2013) 179–184

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Seminars in Pediatric Surgery

journal homepage: www.elsevier.com/locate/sempedsurg

Neonatal pulmonary physiology

Ryan P. Davis, MD, George B. Mychaliska, MDn
Section of Pediatric Surgery, C.S. Mott Children's Hospital, University of Michigan Health Systems, Ann Arbor, Michigan

a r t i c l e in fo a b s t r a c t

Managing pulmonary issues faced by both term and preterm infants remains a challenge to the practicing
Keywords: pediatric surgeon. An understanding of normal fetal and neonatal pulmonary development and physiology
Neonatal physiology is the cornerstone for understanding the pathophysiology and treatment of many congenital and acquired
Lung development problems in the neonate. Progression through the phases of lung development and the transition to
Lung mechanics postnatal life requires a symphony of complex and overlapping events to work in concert for smooth and
Neonatal respiratory failure successful transition to occur. Pulmonary physiology and oxygen transport in the neonate are similar to
older children; however, there are critical differences that are important to take into consideration when
treating the youngest of patients. Our understanding of fetal and neonatal pulmonary physiology continues
to evolve as the molecular and cellular events governing these processes are better understood. This deeper
understanding has helped to facilitate groundbreaking research, leading to improved technology and
treatment of term and preterm infants. As therapeutics and research continue to advance, a review of
neonatal pulmonary physiology is essential to assist the clinician with his/her management of the wide
variety of challenging congenital and acquired pulmonary disease.
& 2013 Elsevier Inc. All rights reserved.

Managing pulmonary issues faced by both term and premature
infants remains a challenge to the practicing pediatric surgeon. An
understanding of normal fetal and neonatal pulmonary develop-
ment and physiology is the cornerstone for understanding the
pathophysiology and treatment of many congenital and acquired
problems in the neonate. Pulmonary complications remain a major
source of morbidity and mortality for neonates and represent an
evolving area of pioneering research.
Normal lung development
The respiratory system consists of elements of air conduction
and exchange. The uptake of oxygen from the environment and
removal of carbon dioxide serve to maintain cellular aerobic
metabolism and acid–base balance. In order to effectively
perform these processes, normal structural and cellular devel-
opment is essential. The respiratory system normally develops
through five phases: embryonic, pseudoglandular, canalicular,
saccular, and alveolar. The boundaries between these phases
blend into each other with overlap at any given time point
between areas of the lung and vary temporally among
individuals.1
Embryonic phase (3–7 weeks)
Lung growth begins in the third week of gestation with the
outgrowth of a small diverticulum from the ventral wall of the foregut
called the primitive respiratory diverticulum or lung bud. This extends
in the ventral caudal direction into the surrounding mesoderm,
growing anterior and parallel to the primitive esophagus. Within a
few days, the grove between the diverticulum and the foregut closes
with the only luminal attachment remaining at the site of the future
hypopharynx and larynx.2 By gestational day 28, the respiratory
diverticulum bifurcates into the right and left primary bronchial buds
(main stem).3 This is followed by a second round of branching
occurring around the fifth week, yielding the secondary bronchial
buds. Finally, the third branching takes place during the sixth week
postconception, producing 10 tertiary bronchi on the right and eight
on the left. The vascular components of the respiratory system also
begin to develop with the pulmonary arteries forming as branches off
the sixth aortic arch while the pulmonary veins emerge from the
developing heart.3 The primitive lung bud is lined by epithelium
derived from endoderm, which will become the epithelium lining the
airways and alveoli. The lung buds grow into the surrounding
mesodermal cells that will differentiate into the blood vessels, smooth
muscle, cartilage, and other connective tissue. Ectoderm will even-
tually give rise to the innervation of the lung.1

n
Pseudoglandular phase (5–17 weeks)
Correspondence to: Section of Pediatric Surgery, C.S. Mott Children's Hospital,
University of Michigan Medical School, 1540 E. Hospital Dr, SPC 4211, Ann Arbor,
Michigan 48109. In the pseudoglandular phase, the lung is composed of multiple
E-mail address: mychalis@med.umich.edu (G.B. Mychaliska). epithelial tubules surrounded by extensive regions of mesenchyme,

1055-8586/$ - see front matter & 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1053/j.sempedsurg.2013.10.005
180 R.P. Davis, G.B. Mychaliska / Seminars in Pediatric Surgery 22 (2013) 179–184
giving a glandular appearance. Cellular proliferation rate increases
during this stage and by postconception week 16, all bronchial
divisions are completed with further growth occurring only by
elongation and widening of existing airways. The intrapulmonary
arterial system develops branching in parallel with the bronchial and
bronchiolar tubules. The respiratory epithelium begins to differ-
entiate with cilia appearing in the proximal airways and cartilage
begins to develop to support the airways.1 Concurrently, closure of
the pleuroperitoneal folds is completed.
Canalicular stage (16–26 weeks)
During the canalicular stage, the capillary beds rapidly expand
with condensation and thinning of the mesenchyme, starting the
first critical step in the formation of the gas exchange regions of
the lung. The ingrowth of capillaries results in thinning in one
population of overlying epithelial cells, narrowing the air–blood
interface, and differentiating into type I pneumocytes that make
up the alveolar wall. In other overlying epithelial cells, lamellar
bodies associated with surfactant synthesis appear, identifying
type II pneumocytes. The airways continue to develop with
completion of the airways through the level of the terminal
bronchioles with their associated acinus.
Saccular stage (24–38 weeks)
The terminal clusters of acinar tubules and buds dilate and
expand into transitory alveolar saccules and ducts with a marked
reduction of the surrounding mesenchymal tissue. By 24 weeks,
there is a sufficiently thin alveolocapillary membrane distance
(0.6 mm) to participate in gas exchange with the efficacy of
exchange being determined beyond this point by the total surface
area available for exchange.3 By the end of this stage, three
additional generations of alveolar ducts have formed and the
conducting airways have developed mucous and ciliated cells.
Overall, cell proliferation slows and ultrastructural cytodiffereni-
tation occurs. The saccules consist of smooth-walled airspaces and
a thick interstitial space. Type II epithelial cells continue to mature
and there is an increase in surfactant synthesis, but overall syn-
thesis levels remain low.
Alveolar stage (36 weeks–8 years)
This is the final stage of lung development and is characterized
by the formation of secondary alveolar septa that divide the
terminal ducts and saccules into true alveolar ducts and alveoli.
There is maturation of the alveolar–capillary membrane, which
increases the surface area for gas exchange. As the terminal saccule
restructures during this stage the double capillary networks fuse,
becoming a single capillary network with each capillary being
simultaneously exposed to at least two alveoli. The barrier to gas
exchange thins to a few nanometers. Type I and type II cells
increase in number, but only type II cells are proliferating actively
suggesting that type I cells are derived from type II cells.3 When
alveolization is complete by 8 years of age, further lung growth
occurs by increasing alveolar size.
Glucocorticoids
A major advance in the treatment of prematurity has been the
maternal administration of glucocorticoids in pregnant women
with preterm labor after 24 weeks in order to promote surfactant
production and maturation of the fetal lung.4,5 The exact mecha-
nism remains unknown; however, studies have shown that ana-
tomic maturation, in particular thinning of the alveolar wall, and
synthesis of mRNAs encoding surfactant proteins increase after
steroid administration.6–8
Physiologic control of lung growth before and after birth
While the fetus and neonate proceed through the phases of
lung growth and development, physiologic and physical factors
play an important role in directing this growth. While not all
factors affecting this process are well understood, the role of fetal
lung fluid and mechanical distension appear to play critical roles.
During fetal life, the lung produces a unique fluid, fetal lung fluid
(FLF), that is a result of net transpithelial chloride and sodium flux
and is produced within the lungs and leaves via the trachea.9 As
the fluid moves from the lung toward the oropharynx, it is either
swallowed or contributes to amniotic fluid. Throughout gestation
the volume of FLF increases10 and keeps the airway distended in
order to stimulate growth.
The volume of FLF is primarily regulated by the resistance to
lung liquid efflux through the upper airways and by fetal breathing
movements (FBM), which include the associated diaphragmatic
activity, and is largely independent of production. When there
is no FBM (apnea), the transpulmonary pressure is usually 1–2 mmHg
above the amniotic sac pressure due to the elastic recoil of the
chest wall. Lung fluid efflux is prevented by high resistance of the
upper airways which prevents FLF loss and maintains an approx-
imately 2 mmHg distending pressure and fetal lung expansion.11
During periods of FBM, the larynx actively dilates to decrease the
resistance to FLF efflux, allowing fluid to leave at an increased rate.
To compensate during periods of FBM, rhythmic contraction of the
diaphragm slows the loss of lung fluid and helps to maintain lung
expansion during periods of low upper airway resistance, demon-
strating that FBM serve to maintain lung expansion and promote
lung growth. Sustained reduction of fetal lung expansion can slow
the structural development of both the vascular bed and alveolar
epithelial cell phenotypes. On the other hand, prolonged over-
expansion of the fetal lungs via tracheal occlusion is a potent
stimulator for fetal lung growth and tissue remodeling.12 Addi-
tionally, it has been observed that fetal airways undergo peristaltic
contractions similar to the gut, which move intraluminal contents
distally and cause expansion of end buds, which also likely play a
role in fetal lung growth and expansion.13
Gas exchange and oxygen transport and delivery
The most important function of the respiratory system is to
uptake oxygen from the environment in order to allow for aerobic
metabolism to meet the changing energy demands of the fetus and
neonate. In neonates, the ability to receive adequate oxygen
delivery depends on the partial pressure of oxygen in inspired
air, ventilation and perfusion matching, hemoglobin concentration
and affinity, cardiac output, and blood volume.14 While the fetal
oxygen transport system is set up to provide optimal oxygen
delivery and has the capacity to adjust delivery to match demand
in the setting of the intra-uterine environment, this system can be
stressed as it adjusts to life outside the womb. The delivery of
oxygen to tissues depends on the pressure gradient between the
blood and the mitochondria and varies with regional oxygen
delivery, tissue oxygen consumption, and hemoglobin–oxygen
affinity.
Oxygen is transported through the blood stream either dis-
solved in aqueous solution or bound to hemoglobin. Arterial
oxygen content can be calculated using the following formula:
arterial oxygen content ¼ (Hgb  1.36  SaO2) þ (0.0031 
PaO2), where Hgb is hemoglobin concentration in grams, SaO2 is
 R.P. Davis, G.B. Mychaliska / Seminars in Pediatric Surgery 22 (2013) 179–184
100
Ar Increased O affinity
te 80 - Alkalosis
- Hypothermia
ria Decreased O affinity
- Decreased 2,3 DPG - Acidosis
l - Fetal Hb - Hyperthermia
ox 60 - Increased 2,3 DPG
yg
en
Sa 40
tu
ra
o
20
n begin to actively absorb it back into the fetal circulation. This
0
20 40 60 80 100
Paral Pressure of oxygen
Fig. 1. The oxygen dissociation curve shows the percent saturation of Hgb at
various partial pressure of oxygen and demonstrates the equilibrium between
oxyhemoglobin and deoxyhemoglobin. The sigmoidal shape is a result of the
cooperative binding between the four hemoglobin polypeptide chains. An impor-
tant point is the P50, which is the partial pressure of oxygen at which erythrocytes
are 50% saturated with oxygen. When oxygen partial pressure is high, such as in the
lungs, hemoglobin binds oxygen with increased affinity. When the partial pressure
of oxygen decreases such as in the peripheral tissues, oxygen is preferentially
unloaded. Multiple factors including acid–base, temperature, and 2,3 DPG affect
hemoglobin's affinity for oxygen, shifting the curve, resulting in more or less
unloading of oxygen at a given partial pressure.
the arterial saturation of hemoglobin, and PaO2 is the arterial
partial pressure of oxygen.1 If hemoglobin is 100% saturated, then
1 g of hemoglobin can deliver 1.36 ml of oxygen. The actual
amount of oxygen carried by hemoglobin is variable and is defined
by the hemoglobin dissociation curve (Figure 1). Normally, hemo-
globin is close to 100% saturated; however, the sigmoidal nature of
the curve ensures that the hemoglobin saturation remains high
even at low PaO2 levels. The hemoglobin dissociation curve is not
static, and hemoglobin's affinity for oxygen can be influenced by a
number of factors. Hemoglobin has an increased affinity for oxy-
gen with a left shift of the oxygen dissociation curve in cases of
alkalosis, hypothermia, decreased 2,3 diphosphoglycerate (DPG),
or fetal hemoglobin. Hemoglobin's affinity for oxygen decreases in
the setting of acidosis, hyperthermia, or increased 2,3 DPG. This
facilitates unloading of oxygen to the peripheral tissues.
Fetal hemoglobin plays an important role in the transport and
unloading of oxygen in the fetal and neonatal periods. Human
hemoglobin consists of three basic chain structures that include
the α chain, β chain, and γ chain, which make hemoglobin A (HgA)
of α2β2 and hemoglobin F (HgF) of α2γ2. The β and γ chains differ
from each other by a few amino acid residues. Fetal hemoglobin
has a significantly higher affinity for oxygen, which favors uptake
of hemoglobin across the placenta. Near term, there is a period of
accelerated erythropoiesis during which HbA synthesis predom-
inates with a gradual and orderly transition in synthesis from γ to β
hemoglobin chains.15
At birth, the oxygen demand in the infant increases by 100–
150%. Consequently, fetal hemoglobin with its increased oxygen
affinity, which was adequate for a fetus, does not provide enough
oxygen diffusion and delivery in the neonate. Post-natally, the
infant's affinity decreases rapidly and reaches normal adult values
by 4–6 months, which corresponds to the amount of time
necessary for the replacement of fetal hemoglobin by adult
hemoglobin.14 The amount of HbF decreases from around 75% to
approximately 2% during the first year of life. Until this occurs,
181
other mechanisms help the neonate to cope with the postnatal
environment. One of the most important phenomenon is an
increase in the concentration of 2,3 DPG during the first few days
of life. This increase has a small direct effect on fetal hemoglobin
but also lowers the intracellular pH and thus decreases hemoglo-
bin's affinity for oxygen.16
Transition to postnatal life
One of the most critical and fascinating periods in human
physiology is the changes that occur, usually in a matter of
minutes, which allow a human to transition from surviving in
the uterine environment to the postnatal environment. Around the
time of birth, epithelial cells cease production of lung fluid and
process is facilitated by active sodium transport that is stimulated
by thyroid hormone, glucocorticoids, and epinephrine.1 During the
first breaths, pulmonary arterial pO2 increase and pCO2 decrease,
resulting in pulmonary vascular dilation, decreased pulmonary
vascular resistance, and constriction of the ductus arteriosus.
Cessation of umbilical blood flow results in closure of the ductus
venosus and increase in systemic vascular resistance. This
increases the left-sided heart pressures and closes the foramen
ovale. With these changes, the transition to postnatal circulation is
complete and the process of postnatal pulmonary dependence is
initiated.
In order for gas exchange to occur in the developing lung, there
needs to be intimate contact between atmospheric oxygen and
capillary blood flow. This requires adequate alveolar ventilation
and pulmonary blood flow. The neonate has a number of physio-
logic mechanisms that allow for matching alveolar ventilation
(V) and pulmonary perfusion (Q) to optimize gas exchange. To
accomplish this, an adequate alveolar gas volume and functional
residual capacity (FRC) must be established shortly after birth and
sustained. Once the FRC is established, this serves as an intra-
pulmonary pool of oxygen. However, newborns are at an increased
risk for hypoxemia due to lower pO2 than adults with less intra-
vascular reserve, FRC closer to airway closure, and high metabolic
demand in infancy resulting in quicker depletion of oxygen
stores.17
Surfactant
While many factors play a critical role in allowing for a smooth
transition to postnatal gas exchange, one of the most clinically
relevant is surfactant. A critical concept in pulmonary physiology is
surface tension and its effects on the pressure drop across an
interface separating two phases of matter, which was defined in
the early 1800s by Young and Laplace.18 The pressure drop
necessary to maintain or inflate air sacs of a given size is propor-
tional to its surface tension and inversely proportional to its radius.
The work of breathing is consequently directly proportional to the
surface tension. During development, surfactant production
increases as type II pneumocytes mature and alveoli increase in
size. Surfactant is a mixture of phospholipids, neutral lipids, and
specific proteins, which by virtue of the amphipathic nature
decreases surface tension, stabilizes small alveoli, improves overall
alveolar inflation, reduces the hydrostatic driving force for pulmo-
nary edema, and decreases work of breathing. When deficient, it
can lead to severe respiratory failure. Exogenous administration
has proven effective in prophylactic or rescue treatment for
respiratory distress syndrome (RDS) in premature infants with a
40% reduction in death and a 30–50% reduction in the odds of
pulmonary air leaks.19
182 R.P. Davis, G.B. Mychaliska / Seminars in Pediatric Surgery 22 (2013) 179–184

Inspiratory
Inspiratory
reserve
capacity
volume

Tidal Volume

Vital Total
capacity lung
capacity
Expiratory
reserve
Funconal volume
residual
capacity
Residual
volume

Fig. 2. Lung measurements: Tidal volume (TV) is the amount of gas moved during one normal inspiration and expiration. Functional residual capacity (FRC) represents the
volume of gas left in the lung following normal expiration. Inspiratory capacity is the maximum volume of air which can be inspired following a normal expiration.
Inspiratory reserve volume is the additional amount of air which can be inspired following normal inspiration. Expiratory reserve volume is the additional amount of air
which can be expired following normal expiration. Residual volume is the minimum lung volume possible, which is the air which remains in the lung following maximum
expiration. Vital capacity is the maximum amount of air which can be moved, maximum inspiration following maximum expiration. Total lung capacity is the total amount of
volume present in the lung.

Lung function and mechanics
Knowledge of static lung measurements (Figure 2) is essential
to understand the physiology, pathophysiology, and response to
therapeutic intervention. Tidal volume, vital capacity, inspiratory
capacity, inspiratory reserve volume, and expiratory reserve vol-
ume can be measured directly using spirometer. On the other
hand, total lung volume, FRC, and residual volume require speci-
alized techniques.1 Over the last 50 years, technological advances
have allowed for measurements of neonatal lung function to move
from the bench to the clinic with new ventilators able to provide
breath-to-breath analysis of lung function. Alterations in FRC occur
in many different disease states and alter gas exchange. Clinically
important disease states, such as respiratory distress syndrome
(RDS), pneumonia, and hypoventilation secondary to pain, cause
reductions in FRC and decrease the oxygen reservoir available
impairing gas exchange. Treatments for decreased FRC include
recruiting collapsed units of lung with positive pressure, increas-
ing FRC, and increasing the oxygen reservoir available for gas
exchange.
The mechanical properties of the lung play an important role in
neonatal respiratory physiology. The lung has physical properties
that resist inflation including recoil, resistance, and inertance, with
the dynamic interaction between these processes being respon-
sible for the effort required during normal spontaneous breath-
ing.2 Elastic recoil is a property of the elastic lung tissue which
must be stretched for lung inflation to occur. According to Hooke's
law, the pressure needed to inflate the lung must be in proportion
to the volume of inflation. The change in volume divided by
change in pressure is the lung compliance. Dynamic compliance
is the volume change divided by the peak inspiratory transthoracic
pressure. Static compliance is volume change divided by peak
inspiratory pressure.20 Throughout the range of normal tidal
volumes, this relationship is linear and starts to plateau at large
lung volumes (Figure 3). On a static compliance curve, ventilation
normally occurs in the steep portion where large changes in
volume occur for small changes in pressure. This is not true at
high or low lung volumes where large changes in pressure are
necessary for smaller changes in volume.
The total compliance for the pulmonary system is made up of
the compliance of the lung and chest wall. The relationship can be
expressed by the following equation: respiratory system compli-
ance (CRS) ¼ 1/chest wall compliance (CCW) þ 1/lung compliance
(CL).2 The desire for the lung to collapse is balanced by the
outward elastic recoil of the chest wall, with FRC occurring at
the end of expiration when these forces are in equilibrium. In
infants, the chest wall is composed primarily of cartilage and thus
the CCW is greater in the infant and the pleural pressure is less
negative. As a result of the more compliant chest wall, the
neonatal lung appears more prone to collapse.21 FRC is maintained
in newborns by increasing expiratory resistance through laryngeal
abduction, maintaining inspiratory muscle activation throughout
expiration, and initiating high breathing frequencies to limit
expiration time.22 The FRC is reduced with edema, surfactant
deficiency, and decreased alveolar radius.
Resistance to gas flow is also an important determinant of
pulmonary gas movement in the neonate. Resistance to airflow
High FRC
Vo
lu Normal FRC
m
e
Low FRC
Pressure
Fig. 3. A static compliance curve demonstrating the relationship between changes
in volume over pressure within a normal lung. Superimposed are dynamic flow–
volume loops. At normal FRC in the steep portion of the curve, smaller changes in
pressure result in greater changes in volume. At large FRC, such as with mechanical
ventilation, or low FRC, such as atelectasis, the dynamic flow–volume loops show
that a larger change in pressure is required to generate changes in volume.
 R.P. Davis, G.B. Mychaliska / Seminars in Pediatric Surgery 22 (2013) 179–184
arises due to friction between gas molecules and the walls of the
airway and because of friction between the tissues of the lung and
the chest wall. The airway resistance makes up a significantly
greater proportion of the resistance, making up approximately 80%
of the total resistance, with 50% of the airway resistance.23 During
laminar flow, the pressure difference necessary for gas to flow
through the airway is directly proportional to flow times a rate
constant–airway resistance.2 During turbulent flow, which occurs
at branch points, sites of obstruction, and high flow, the pressure
necessary to move air is directly proportional to a constant times
the flow rate squared. This constant is directly proportional to the
volumetric flow rate and gas density and is inversely proportional
to the radius of the airway and gas viscosity. Airway diameter is
possibly the most important clinical factor affecting airway resist-
ance, because airway resistance varies inversely with radius to the
fourth or fifth power. Airway resistance is decreased during
inspiration as the pleural pressure becomes negative due to
expansion of the chest wall, which increases airway and alveolar
diameter and decreases resistance. During expiration, the pleural
pressure increases and the airways are compressed. Collapse is
prevented by cartilage and gas pressure in the lumen, which can
become a problem especially in small preterm infants with poorly
supported central airways.
Assisted ventilation
Pediatric surgeons encounter many clinical scenarios where
neonates require assisted ventilation. Neonatal respiratory failure
has been treated with mechanical ventilation since the 1960s.24
Initially, adult ventilators were modified for neonatal use. The first
devices designed for neonates were continuous flow, time-cycled,
pressure-limited devices to provide intermittent mandatory ven-
tilation (IMV).25 There were many limitations to these ventilators
as physicians could only vary fraction of inspired oxygen, peak
inspiratory pressure, positive end-expiratory pressure, inspiratory
time, rate, and circuit flow. In the 1980s, high-frequency jet
ventilation (HFJV) was introduced. During the 1990s, microproc-
essors were incorporated into neonatal ventilators, greatly
expanding the scope of neonatal ventilation with clinicians able
to control a greater number of variables, including target modality,
mode of ventilation, minute ventilation, cycling mechanism, assist
sensitivity, and rise time with light-weight transducers giving real-
time breath-to-breath information allowing easier adjustment of
ventilator settings depending on patient illness.26
Currently, ventilators in clinical use are classified as either
those which deliver tidal ventilation (conventional) or devices
which deliver smaller gas volumes at rapid rates (high-frequency
ventilators). Conventional ventilators have significantly improved
over recent years with the addition of microprocessor chips. They
continue to have standard modes of ventilation including inter-
mittent mandatory ventilation (IMV), synchronized intermittent
mandatory ventilation (SIMV), assist-control ventilation (AC), and
pressure support ventilation (PSV). These modalities can be further
modified to deliver either target pressure or volume. Further
Table
Indexes used to determine infants who are eligible to be placed on ECLS.
Index Equation
Oxygenation index (OI) OI ¼ (MAP  FiO2  100)/PaO2
Postductal alveolar-arterial oxygen (A  a)DO2
gradient
Ventilator index (VI) (Respiratory rate  PaCO2  peak inspiratory pressure)/
1000
183
description of conventional ventilators is beyond the scope of
this study; however, the clinical utility of various modalities has
been examined in the recent literature. For example, a recent
meta-analysis of pressure-controlled modalities vs volume-
controlled modalities demonstrated a significant decrease in
pneumothorax and duration of ventilation as well as a decrease
in chronic lung disease (CLD) in preterm infants treated with
volume-controlled modes of ventilation as opposed to pressure-
controlled modes.27
There are two types of high-frequency ventilation: high-
frequency jet ventilation (HFJV) and high-frequency oscillatory
ventilation (HFOV). HFJV provide smaller volumes (1–3 ml/kg)
more often at a much higher rate (240–660 breaths per min)
and expiration is passive. Oxygenation is proportional to mean
airway pressure and ventilation is proportional to amplitude (peak
inspiratory pressure vs PEEP).25 Jet pulsations produce high-
velocity laminar flow that has the ability to bypass airway
disruptions. HVOF differs in that it delivers smaller tidal volumes
(1–2 ml/kg) and at an even faster rate (8–15 Hz). The lung is
inflated to a static volume and then oscillated around the mean
airway pressure.
For infants (generally 434 weeks EGA) who cannot be success-
fully ventilated using these modes of ventilation, extracorporeal
life support (ECLS) is an option. ECLS is indicated in cases of acute
cardiopulmonary failure that is unresponsive to maximal ther-
apy.28 The veno-venous mode provides respiratory support and
the veno-arterial mode provides cardiorespiratory support. ECLS is
used for days to a few weeks in neonates to allow native organ
function to return. Three clinical measurement systems have been
developed to identify these patients (Table), all of which are
associated with extremely high mortality. However, the decision
to initiate ECLS is based on clinical judgment and the patient's
response to maximal medical therapy.
Clinical
Abnormalities in fetal lung growth and development can lead
to a wide range of clinical problems in the newborn period. One of
the most important clinical problems is preterm birth (birth before
37 weeks EGA), which occurs in 11% of births in the United States
and remains the leading cause of morbidity and mortality in
industrialized nations, accounting for 60–80% of deaths in infants
without congenital abnormalities.29 The more premature the
infant, the greater the risk for pulmonary complications;
extremely low gestational age newborns (ELGANs) born before
28 weeks EGA are at the greatest risk. These infants are born at the
transitional period between the canalicular and saccular phases
which in when the air–blood barrier is just beginning to thin to the
point where gas exchange is possible. Despite maternal steroids,
surfactant, and sophisticated ventilatory strategies including new,
less-invasive modalities, respiratory failure and chronic lung dis-
ease in survivors are common. Since extremely premature infants
have underdeveloped lungs not suitable for gas exchange, a novel
solution is to recapitulate the fetal environment with extracorporeal
Evidence
OI 4 40 in 3–5 postductal gases predictive of 80% or greater
mortality32
A (A a)DO2 despite 8 h of maximal therapy predicted 79%
mortality33
VI and OI greater than 40 associated with 77% mortality34
184 R.P. Davis, G.B. Mychaliska / Seminars in Pediatric Surgery 22 (2013) 179–184
support using an artificial placenta, which is being developed in
the laboratory.28,30,31
Neonatal respiratory failure is also caused by congenital
anomalies such as congenital diaphragmatic hernias (CDH).
Although the cause of CDH remains unknown, the consequences
to pulmonary development and function are well known. If the
pleuroperitoneal canal has not closed when the midgut returns to
the abdomen by week 9–10, the abdominal viscera herniate into
the chest cavity. This early herniation affects both the ipsilateral
and contralateral lung development, with hypoplasia more severe
on the ipsilateral side. In addition to pulmonary hypoplasia,
pulmonary vascular beds are also abnormal with a reduction in
the total number of arterial branches in both the ipsilateral and
contralateral pulmonary parenchyma, with significant adventitial
and medial wall thickening noted with a resultant increased risk
for fixed and intractable pulmonary hypertension.1 If the pulmo-
nary vascular resistance remains high after the transition to
postnatal life, right-to-left shunting of blood occurs with delivery
of unsaturated blood to the systemic circulation with resultant
hypoxia. The most significant advance in the treatment of CDH is
the adoption of a “gentle ventilation” strategy. If pulmonary
hypertension is severe, ECLS is the only effective treatment option.
While CDH results in hypoplasia of the lung due to a disruption
of early lung development, other congenital lung lesions (CLL)
including congenital pulmonary airway malformations (CPAMs),
congenital lobar emphysema, and pulmonary sequestrations (PSs)
also form space-occupying lesions during fetal development and
may cause pulmonary hypoplasia or respiratory symptoms at
birth. Giant CPAMs and PSs can cause hydrops before birth and
may cause pulmonary hypoplasia and associated pulmonary
hypertension. However, unlike CDH, most CLL compress a partially
grown lung, and pulmonary hypoplasia is usually not significant.
Congenital lobar emphysema may cause significant air trapping at
birth and requires emergent lobectomy. Most CLL are asympto-
matic at birth, but symptomatic lesions require lobectomy.
Conclusion
Understanding fetal and neonatal pulmonary development and
physiology is important to effectively treat premature and term
neonates with pediatric surgical problems. The transition from
placental to pulmonary support is a symphony of processes that
must be coordinated in order for successful transition. Further
advances in technology will likely allow for more real-time
analysis of pulmonary mechanics and allow for further tailoring
of individualized treatments for complex pathologies. Advances in
extracorporeal support for neonates may further enhance our
ability to treat respiratory failure.
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