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Keywords:
Neonatal physiology
Lung development
Lung mechanics
Neonatal respiratory failure
a b s t r a c t
Managing pulmonary issues faced by both term and preterm infants remains a challenge to the practicing
pediatric surgeon. An understanding of normal fetal and neonatal pulmonary development and physiology
is the cornerstone for understanding the pathophysiology and treatment of many congenital and acquired
problems in the neonate. Progression through the phases of lung development and the transition to
postnatal life requires a symphony of complex and overlapping events to work in concert for smooth and
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.
180
100
Ar
te
ria
l
ox
yg
en
Sa
tu
ra
o
n
80
Increased O anity
- Alkalosis
- Hypothermia
- Decreased 2,3 DPG
- Fetal Hb
60
Decreased O anity
- Acidosis
- Hyperthermia
- Increased 2,3 DPG
181
40
20
20
80
40
60
Paral Pressure of oxygen
100
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 important 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 afnity. When the partial pressure
of oxygen decreases such as in the peripheral tissues, oxygen is preferentially
unloaded. Multiple factors including acidbase, temperature, and 2,3 DPG affect
hemoglobin's afnity for oxygen, shifting the curve, resulting in more or less
unloading of oxygen at a given partial pressure.
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 dened in
the early 1800s by Young and Laplace.18 The pressure drop
necessary to maintain or inate air sacs of a given size is proportional 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
specic proteins, which by virtue of the amphipathic nature
decreases surface tension, stabilizes small alveoli, improves overall
alveolar ination, reduces the hydrostatic driving force for pulmonary edema, and decreases work of breathing. When decient, 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 3050% reduction in the odds of
pulmonary air leaks.19
182
Inspiratory
capacity
Inspiratory
reserve
volume
Tidal Volume
Total
lung
capacity
Vital
capacity
Funconal
residual
capacity
Expiratory
reserve
volume
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.
expressed by the following equation: respiratory system compliance (CRS) 1/chest wall compliance (CCW) 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
deciency, and decreased alveolar radius.
Resistance to gas ow is also an important determinant of
pulmonary gas movement in the neonate. Resistance to airow
High FRC
Vo
lu
m
e
Normal FRC
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 ow
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 owvolume loops show
that a larger change in pressure is required to generate changes in volume.
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 signicantly
greater proportion of the resistance, making up approximately 80%
of the total resistance, with 50% of the airway resistance.23 During
laminar ow, the pressure difference necessary for gas to ow
through the airway is directly proportional to ow times a rate
constantairway resistance.2 During turbulent ow, which occurs
at branch points, sites of obstruction, and high ow, the pressure
necessary to move air is directly proportional to a constant times
the ow rate squared. This constant is directly proportional to the
volumetric ow 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 resistance, because airway resistance varies inversely with radius to the
fourth or fth 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 modied for neonatal use. The rst
devices designed for neonates were continuous ow, time-cycled,
pressure-limited devices to provide intermittent mandatory ventilation (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 ow. In the 1980s, high-frequency jet
ventilation (HFJV) was introduced. During the 1990s, microprocessors 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 realtime breath-to-breath information allowing easier adjustment of
ventilator settings depending on patient illness.26
Currently, ventilators in clinical use are classied as either
those which deliver tidal ventilation (conventional) or devices
which deliver smaller gas volumes at rapid rates (high-frequency
ventilators). Conventional ventilators have signicantly improved
over recent years with the addition of microprocessor chips. They
continue to have standard modes of ventilation including intermittent mandatory ventilation (IMV), synchronized intermittent
mandatory ventilation (SIMV), assist-control ventilation (AC), and
pressure support ventilation (PSV). These modalities can be further
modied to deliver either target pressure or volume. Further
183
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 6080% 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 airblood 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 disease 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
Table
Indexes used to determine infants who are eligible to be placed on ECLS.
Index
Equation
Evidence
(A a)DO2
184
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.
References
1. Wilson JM, DiFiore JW. Respiratory physiology and care. In: Coran AG, Adzick NS,
editors. Pediatric Surgery. 7th ed. Philadelphia, PA: Elsevier Mosby; 2012.
p. 109123.
2. Fraga MV, Guttentag S. Lung development. In: A. Christine, aSUD Gleason,
editors. Averys Diseases of the Newborn. Los Angeles, CA: Elsevier/Saunders;
2012. p. 571583.
3. Wert SE. Normal and abnormal structural development of the lung. In: Polin
RA, Fox WW, Abman SH, editors. Fetal and Neonatal Physiology. 4th ed.,
Philadelphia, PA: Elsevier/Saunders; 2011.
4. Morrison JL, Botting KJ, Soo PS, et al. Antenatal steroids and the IUGR fetus: are
exposure and physiological effects on the lung and cardiovascular system the
same as in normally grown fetuses? J Pregnancy. 2012;2012(1):839656.