Downloaded from http://fn.bmj.com/ on November 8, 2015 - Published by group.bmj.
com
ADC-FNN Online First, published on November 5, 2015 as 10.1136/archdischild-2013-305704
1
Ritchie Centre, Hudson
Institute of Medical Research,
Melbourne, Victoria, Australia
2
Department of Obstetrics &
Gynaecology, Monash
University, Melbourne, Victoria,
Australia
3
Department of Pediatrics,
Leiden University Medical
Centre, Leiden, The
Netherlands
4
School of Physics and
Astronomy, Monash University,
Melbourne, Victoria, Australia
Correspondence to
Professor Stuart B Hooper, The
Ritchie Centre, Hudson
Institute of Medical Research,
27-31 Wright St, Clayton, VIC
3168, Australia; stuart.
hooper@monash.edu
Received 24 June 2015
Revised 30 September 2015
Accepted 8 October 2015
To cite: Hooper SB, te
Pas AB, Kitchen MJ. Arch
Dis Child Fetal Neonatal Ed
Published Online First:
[please include Day Month
Year] doi:10.1136/
archdischild-2013-305704
Hooper SB, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1F6. doi:10.1136/archdischild-2013-305704
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.
Review
Respiratory transition in the newborn: a three-phase
process
Stuart B Hooper,1,2 Arjan B te Pas,3 Marcus J Kitchen4
ABSTRACT
We propose that the respiratory transition at birth passes
through three distinct, but overlapping phases, which
reect different physiological states of the lung.
Accordingly, respiratory support given to infants should
be optimised to suit the underlying physiological state of
the lung as it passes through each phase. During the
rst phase, the airways are liquid-lled and so no
pulmonary gas exchange can occur. Respiratory support
should, therefore, be focused on clearing the gas
exchange regions of liquid. In the absence of gas
exchange, little or no CO2 will accumulate within the
airways and, therefore, interrupting ination pressures to
allow the lung to deate and exhale CO2 is unnecessary.
This is the primary rationale for administering a
sustained ination at birth. During the second phase, the
gas exchange regions are mostly cleared of liquid,
allowing pulmonary gas exchange to commence.
However, the liquid cleared from the airways resides
within the tissue during this phase, which increases
perialveolar interstitial tissue pressures and the risk of
liquid re-entry back into the airways. As a result,
respiratory support should be optimised to minimise
alveolar re-ooding during expiration, which can be
achieved by applying an end-expiratory pressure. The
third and nal phase occurs when the liquid is
eventually cleared from lung tissue. Although gas
exchange may be restricted by lung immaturity, injury
and inammation during this phase, considerations of
how fetal lung liquid can adversely affect lung function
are no longer relevant.
INTRODUCTION
As the future airways of the fetal lungs are liquid-
lled and gas exchange occurs across the placenta
before birth, the site of gas exchange must immedi-
ately switch to the lungs after birth as soon as the
umbilical cord is clamped.13 To achieve this,
the airways must be rapidly cleared of liquid so that
the lungs can aerate. However, lung aeration is not
only critical for pulmonary gas exchange as it is
also responsible for initiating the cardiovascular
changes at birth, which together underpin the tran-
sition to newborn life.1 3 As such, lung aeration is
the critical central event that initiates a sequence of
interdependent physiological changes that enable
the infant to transition to independent life after
birth.
Failure to adequately clear the airways of lung
liquid at birth is a major cause of neonatal morbid-
ity and mortality, particularly in very preterm
infants.4 5 As a result, these infants usually require
some form of respiratory support, which com-
monly involves the application of positive pressure
ventilation, applied either non-invasively (via a face
mask) or following intubation of the trachea.68
However, there is still considerable debate as to
how this respiratory support should be delivered.8
Recent advances in our understanding of the
mechanisms regulating lung aeration at birth9 10
have provided new insights as to how this process
can be facilitated in newborn infants. However, the
current focus is almost entirely on gas exchange
with little or no attention applied to facilitating
airway liquid clearance, uniform lung aeration or
preventing alveolar re-ooding during the immedi-
ate newborn period. While gas exchange is the
primary consideration, these additional factors
should not be overlooked as they greatly impact on
the capacity of the lung to exchange respiratory
gases. In this review, we will discuss recent
advances in our understanding of the factors
driving airway liquid clearance and propose a new
approach for supporting pulmonary ventilation at
birth. Specically, we suggest that the respiratory
transition occurs in three phases and that any
respiratory support provided requires different
approaches to be effective in each phase (gure 1).
We propose that:
1. The rst phase involves airway liquid clearance
and principally involves the movement of
liquid through the airways and across the distal
airway wall. As gas exchange is not possible
during much of this phase, because the distal
airways are liquid-lled, the focus should be on
moving liquid through the airways with the
goal of uniformly aerating gas exchange
regions (gure 1).
2. The second phase overlaps with and occurs as a
direct result of the rst phase, whereby liquid
leaving the airways temporarily accumulates
within the interstitial tissue compartment. This
transiently increases interstitial tissue pressures
and the probability of liquid re-entry into the
airways, thereby compromising gas exchange
(gure 1).
3. The third and nal phase occurs when the
liquid has been cleared from the tissue,
although there is likely to be much overlap with
phase 2 in different regions of the lung, at least
during the initial stages. During this phase,
respiratory support can primarily focus on gas
exchange, uniform ventilation and maintaining
respiratory homeostasis (gure 1).
Currently, the recommended approach is unidi-
mensional, mainly focusing on strategies applicable
for an already aerated lung that is not water-
logged. We suggest that the respiratory support
provided to an infant should be consistent with the
physiological state of the lung and vary depending
upon the phase of transition.
F1
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Review

Figure 1 The lung passes through three distinct phases as it transitions from a liquid-lled organ with a low blood ow into the sole organ of gas
exchange after birth. During the rst phase, the liquid-lled airways must be cleared of lung liquid so that gas exchange can commence. Airway
liquid clearance primarily results from transepithelial pressure gradients generated during inspiration, which provides the pressure gradient for liquid
to move from the upper into the lower airways and then across the epithelium into the surrounding lung tissue. In most infants, it is likely that this
phase is very short in duration (ie, seconds), but can extend for many minutes, which will be reected by continuing low oxygenation and heart
rates immediately after birth. During the second phase, the liquid cleared from the airways resides within the interstitial tissue, which increases
interstitial tissue pressures and increases the likelihood of liquid re-entering the airways at end-expiration (ie, at functional residual capacity). As
liquid clearance from lung tissue is much slower than it is from the airways, this phase can last for hours (4 h); however, application of a positive
end-expiratory pressure will reduce the pressure gradient for airway liquid re-entry. The third phase depicts the lung following all airway liquid
clearance from the chest, resulting in subatmospheric interstitial tissue pressures and the generation of end-expiratory pressure gradients, which
assist in keeping the airways cleared of liquid. Al, alveolus; BV, blood vessels; P, pressure.

PHASE 1: AIRWAY LIQUID CLEARANCE
There has been considerable debate in the literature about the
mechanisms of airway liquid clearance at birth and the timing at
which this process commences.6 11 12 Nevertheless, when taken
altogether (see below), it is evident that airway liquid clearance
can occur due to a variety of different mechanisms.6 However,
in any one infant, the mechanism that provides the greatest con-
tribution will likely differ depending on the timing (gestational
age) and mode of delivery (vaginal vs caesarean section (CS)
delivery).
LIQUID CLEARANCE BEFORE BIRTH
While it has been suggested that airway liquid volumes can
decrease days before birth,5 13 this has not been conrmed in
pregnancies with established normal amniotic uid volumes.14
Oligohydramnios is known to reduce lung liquid volumes due
to an increase in transpulmonary pressure, causing the loss of
lung liquid.15 Similarly, any situation that reduces the available
intrauterine space, such as the presence of a twin, may reduce
lung liquid volumes before labour onset. However, when con-
sidered in relation to the lungs capacity to clear airway liquid
after birth (see below), this debate appears somewhat esoteric
unless the infant is delivered by CS. In this situation, the
mechanisms for airway liquid clearance during birth are absent,
necessitating that all airway liquid is cleared across the airway
epithelium, with little being lost via the nose and mouth.4
LIQUID CLEARANCE DURING BIRTH
Fetal postural changes
Numerous reports in the literature have described the loss of
large volumes of liquid via the nose and mouth following
F2 Hooper SB, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1F6. doi:10.1136/archdischild-2013-305704
delivery of the infants head.6 16 This mechanism of lung liquid
loss is commonly referred to as vaginal squeeze. However, this
description is not entirely accurate as the infants chest offers
little resistance to delivery compared with the head and
shoulders.17 Instead, it is thought that uterine contractions force
a change in fetal posture, which greatly increases fetal spinal
exion.15 As for oligohydramnios, this increases abdominal
pressure, which increases transpulmonary pressure by elevating
the diaphragm, resulting in lung liquid loss via the nose and
mouth. This process likely explains the gushes of liquid that
have been observed following delivery of the infants head.
Na reabsorption
Until recently, the primary mechanism responsible for airway
liquid clearance at birth was thought to result from Na+ uptake
across the airway epithelium, which reverses the osmotic gradi-
ent leading to airway liquid reabsorption.5 This mechanism is
stimulated by increased circulating adrenaline and vasopressin
levels, released in response to the stress of labour, and provides
a convenient explanation for why infants born by CS have a
higher risk of transient tachypnoea of the newborn (TTN; wet
lung).4 5 However, this mechanism only develops in late gesta-
tion and is absent in the immature lung of preterm infants, as
RNA transcripts encoding epithelial Na channels (ENaC) subu-
nits are virtually undetectable in the immature human lung.18
Clearly, preterm infants cannot use this mechanism to clear
airway liquid.19 20
Although adrenaline and vasopressin infusions inhibit lung
liquid secretion and activate liquid reabsorption late in gesta-
tion,2123 pharmacological doses are required to achieve liquid
reabsorption.22 24 Furthermore, based on the measured
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reabsorption rates achieved, it would take hours to clear all
liquid2123 and adrenaline would have to remain elevated
throughout this time.25 However, normal healthy infants can
clear their airways of liquid and establish effective gas exchange
within seconds to minutes of birth.20 26 27 Similarly, although
heart rates commonly increase (from 100 to 160 bpm) after
birth,28 there is no evidence of a sustained tachycardia,28 which
would be expected during a sustained stress-induced catechol-
amine release.
While there is considerable evidence indicating that ENaCs
help to control airway liquid in an aerated lung,18 29 their role
in airway liquid clearance at birth is less certain. Indeed, while
inhibiting ENaC activity with amiloride delays lung liquid clear-
ance in spontaneously breathing newborns, it does not prevent
it and its effect in ventilated newborns is restricted to the expira-
tory phase.30 ENaCs are encoded by three different genes (-,
- and -), with the mature protein comprised of three subu-
nits.18 As -ENaC knockout mice died of respiratory failure
within 40 h of birth and had increased lung wet weights, it was
assumed that deletion of the -ENaC gene disrupted airway
liquid clearance.31 However, these newborn mice also had weak
inspiratory activity,18 which likely contributed to respiratory
failure, as respiratory function is a major determinant of lung
aeration at birth.9 10 Indeed, deletion of -ENaC or -ENaC
subunits does not cause respiratory failure despite reducing
ENaC activity sixfold.18 Similarly, infants with gene mutations
that markedly reduce ENaC activity ( pseudoaldosteronism) do
not suffer respiratory failure at birth.32
LIQUID CLEARANCE AFTER BIRTH
While the mode and timing of delivery must inuence the volume
of airway liquid, at birth liquid must partly ll the airways as air is
unlikely to enter the distal airways before the head is delivered. As
such, a signicant amount of liquid must be cleared after birth,
particularly from the distal airways, but until recently, the role of
postnatal mechanisms has been largely overlooked as a major
mechanism driving airway liquid clearance. Indeed, recent studies
indicate that respiratory activity plays the nal and most signicant
role in airway liquid clearance9 10 at birth.
Role of respiratory activity
Using phase-contrast X-ray imaging, the entry of air into the
lungs after birth has been imaged to study the temporal and
spatial pattern of lung aeration. These studies demonstrate that
lung aeration mostly (95%) occurs during inspiration, in spon-
taneously breathing term newborn rabbits, with no liquid clear-
ance occurring between breaths; movies can be viewed at http://
www.neoresus.org.au/pages/LM1-7-Breathing.php#B_
FirstBreaths and http://www.fasebj.org/cgi/content/full/fj.
07-8208com/DC1.9 10 Instead, the air/liquid interface tended to
move proximally between breaths, reecting liquid re-entry into
the airways and a gradual decline in functional residual capacity
(FRC). As amiloride increases the rate of FRC decrease,30 Na
reabsorption may assist in maintaining FRC by minimising
liquid re-entry into the airways between breaths. Lung aeration
and FRC accumulation only occurred during inspirations, result-
ing in a stepwise increase in FRC with each breath.9 10 The
FRC increase per breath varied, but was as high as 3 mL/kg in
some newborns, resulting in an FRC of 15 mL/kg after ve
breaths, over 30 s.9 10 Thus, with an inspiratory time of 0.3
s, these newborn rabbits cleared airway liquid at a rate of
9 mL/kg/s (or 32 L/kg/h) during inspiration, which is consid-
erably greater than what can be achieved with adrenaline
(maximum of 10 mL/kg/h).2123
Hooper SB, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1F6. doi:10.1136/archdischild-2013-305704
Review
Inspiration-induced airway liquid clearance is thought to
result from an increase in the transepithelial pressure gradi-
ent.9 10 This gradient is generated by inspiratory muscles, which
reduce intrapleural and interstitial tissue pressures by expanding
the chest wall. This produces a pressure gradient across the
airway wall, between the interstitial tissue and airway lumen, as
well as between the upper and lower airways. As a result, liquid
is driven from the proximal into the distal airways from where
it is cleared across the distal airway wall into the surrounding
interstitial tissue space.
Facilitating airway liquid clearance after birth
Recognising that increased transepithelial pressure gradients
drive airway liquid clearance has provided a new understanding
for how lung liquid clearance can be facilitated in preterm
infants.11 While inspiration generates the pressure gradients
across the airway wall by creating subatmospheric pressures
within perialveolar tissue, numerically similar pressure gradients
can be achieved by applying positive pressures to the airways.30
This is commonly achieved by applying intermittent positive
pressure ventilation via a facemask, with inspiratory times of
0.30.5 s. However, it is questionable whether this is the most
appropriate ventilation strategy. Indeed, the principal goal at
this stage of resuscitation is to clear the airways of liquid
because gas exchange is prevented due to the presence of liquid
in the distal airways (gure 1). As the viscosity of liquid is con-
siderably higher than air, the airway resistance is 100 times
higher when the lung is liquid-lled versus when it is air-lled.
It is for this reason that the resistance decreases and lung com-
pliance markedly increases as the lung aerates after birth.33 34
Due to the high resistance of moving liquid through the
airways relative to air, either higher pressures or longer ination
times are required to move the same volume of liquid compared
with air. Since the resistance rapidly decreases as the airways ll
with air, the pressure required to move a xed volume of air
into the lung will also rapidly decrease as the lung aerates.33 34
Thus, using high pressures and short ination times risk over
inating lung regions and causing injury if regions aerate more
quickly than the caregiver expects. Furthermore, as lung aer-
ation in different lung regions occurs at very different rates, aer-
ation across the lung is initially non-uniform and progressively
becomes more uniform as the ination time increases.3335
Thus, air will initially ow rapidly into and inate aerated lung
regions, simply because this is the lowest resistance pathway for
airow, whereas air will only ow into liquid-lled regions
when airway pressure exceeds the pressure required to overcome
the resistance to move liquid through the airways.33 34 As such,
the ow dynamics and tissue mechanics of liquid-lled and
aerated lung regions are vastly different, making it extraordinar-
ily difcult to ventilate without overinating and injuring
aerated lung regions.
The application of long initial ination times greatly increases
the uniformity of lung aeration before the onset of tidal ventila-
tion. While lung aeration continues to occur in a non-uniform
pattern during the sustained ination (SI), if the ination is long
enough, most of the lung will aerate before the ination has
ceased.33 34 This process has been visualised using phase-
contrast X-ray imaging, demonstrating that an SI can uniformly
aerate the lung and fully recruit an FRC and tidal volumes fol-
lowing the onset of tidal ventilation.33 34 This ensures that
during the subsequent tidal ventilation period the incoming air
is uniformly distributed across the lung, thereby reducing the
risk of regional overination. Uniform lung aeration also avoids
F3
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Review
large ventilation-perfusion mismatch, which can occur in a par-
tially aerated lung.36
While there is considerable debate in the literature as to the
efcacy of an SI at birth, recent clinical studies have failed to
show a signicant benet of an SI.37 38 The question, therefore,
arises, why are they effective in animal studies, but not in
human trials? One possible answer is the method of application.
In all animal studies, the SI was applied in intubated animals,
whereas in humans, the SI has been applied non-invasively,
mostly using a facemask.37 38 An analysis of the airow and gas
volume changes during the SI in humans demonstrates that
airow into the lung is greatly restricted unless the infant takes
a breath, indicating the presence of an obstruction.37 While this
could be a consequence of head and mask position, our recent
imaging studies indicate that the glottis may be actively adducted
at birth (gure 2), thereby preventing air from entering the lung
during an SI. It is well established that, before birth, active
glottic adduction during apnoea is an important mechanism for
maintaining lung expansion and lung growth.3941 Thus, if this
pattern of activity persists into the newborn period, then we
should expect apnoeic infants to have an adducted glottis.
PHASE 2: LIQUID ACCUMULATION WITHIN THE LUNGS
INTERSTITIAL TISSUE COMPARTMENT
The process of airway liquid clearance results in liquid move-
ment across the distal airway wall into the surrounding tissue.9
As this mostly occurs during inspiration, the movement of liquid
(9 mL/kg/s) across the epithelium is extremely rapid, resulting
in near complete airway liquid clearance (>15 mL/kg of liquid)
within 35 breaths (over 1530 s) in term spontaneously breath-
ing rabbits.9 On the other hand, clearance of this liquid from
the tissue via the lymphatics and blood vessels is thought to take
considerably longer (46 h).42 As a result, signicant amounts of
liquid reside within the interstitial tissue compartment for the
rst 46 h after birth, essentially resulting in pulmonary
oedema42 (gure 1). As the liquid is accommodated within a
compartment that has a nite volume, this must result in an
increase in pressure within that compartment (gure 1). This
explains why the chest wall expands9 and interstitial tissue pres-
sures increase (to 6 cmH2O)43 immediately after birth.
Interstitial tissue pressures then gradually decrease over the next
46 h to permanently become subatmospheric (at rest).43
Figure 2 Phase-contrast X-ray image of the upper chest, trachea,
larynx and pharynx in a near term (30 days), spontaneously breathing
newborn rabbit. The larynx is closed immediately after birth, which
prevents air from entering the airways during intermittent positive
pressure ventilation, applied via a facemask.
F4 Hooper SB, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1F6. doi:10.1136/archdischild-2013-305704
By elevating interstitial tissue pressures,43 the accumulation of
airway liquid within the lungs interstitial tissue compartment
must increase the hydrostatic driving pressure for liquid to
re-enter the airways.10 As a result, when alveolar pressures
decrease to atmospheric pressure during expiration, liquid tends
to re-enter the airways, albeit much more slowly than its clear-
ance during inspiration due to the smaller pressure gradient
(gure 1). This explains the gradual reduction in FRC that
occurs between breaths in spontaneously breathing term
newborn rabbits immediately after birth.10 30 This airway liquid
is quickly recleared back into the tissue with subsequent inspira-
tions, resulting in a continuous cycle of airway liquid clearance
and re-entry during the breathing cycle.10 It is likely that this
cycle continues until excess liquid is cleared from the tissue (via
lymphatics and vessels) and interstitial tissue pressures become
subatmospheric.42 43 While this may seem inefcient, as the
hydrostatic pressure gradient generated during inspiration (20
80 cmH2O) in term infants44 is much greater than the reverse
gradient during expiration (6 cmH2O),43 the potential to clear
liquid from the airways during inspiration is considerably
greater than the potential for airway liquid re-entry. This is one
reason why the application of positive airway pressures at rest
(positive end-expiratory pressure and continuous positive
airway pressure (CPAP) are important in ventilated and spontan-
eously breathing preterm infants immediately after birth.33 45
That is, by maintaining a positive airway pressure at rest, these
strategies not only assist the compliant chest wall in opposing
lung recoil, but also reduce the hydrostatic pressure gradient for
liquid to move back into the airways (gure 1). In essence, most
newborns also adopt this strategy by invoking expiratory
braking manoeuvres and grunting shortly after birth.10 26 These
manoeuvres increase airway pressures during expiration, which
help to oppose liquid movement back into the airways and
maintain FRC.
TTN; is it consequence of large airway liquid volumes at
birth?
As the majority of liquid residing in the airways at birth is
cleared into the surrounding tissue, the greater the volume of
liquid in the airways, the greater the volume of liquid that must
be temporarily accommodated in the interstitial space immedi-
ately after birth (gure 1). Logically, greater liquid volumes
within the tissue must result in higher interstitial tissue pressures
and, therefore, a greater driving pressure for airway liquid
re-entry. The question of whether there are situations in which
infants are born with larger (or smaller) volumes of liquid in
their airways is an interesting one and is most probably applic-
able to infants born by CS. It is widely considered that term
infants delivered by CS without labour have a higher incidence
of TTN or wet lung because they have not experienced the
stress of labour and the adrenaline-induced activation of Na+
(and liquid) reabsorption.4 29 While this is a convenient explan-
ation that ts nicely with previous concepts for airway liquid
clearance,5 it assumes that Na+ reabsorption is the primary
mechanism involved, which is unlikely (see above). This explan-
ation also ignores other birth-related mechanisms for reducing
airway liquid volumes and cannot explain why millions of
infants born by CS are able to clear their airways of liquid
without any respiratory-related issues.
We suggest that TTN is primarily the result of being born
with larger volumes of airway liquid, resulting in larger volumes
of liquid accumulating in the tissue and a greater potential for
airway liquid re-ooding. We propose that delivery by CS
bypasses the mechanisms detailed above for airway liquid
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clearance during birth, particularly the postural changes. This
increases the likelihood of an infant being delivered with larger
volumes of airway liquid than would otherwise occur if it was
born vaginally. As this liquid has to eventually be accommodated
in the tissue,42 this will result in higher interstitial tissue pres-
sures43 and increase the potential for liquid re-ooding back
into the airways. This, in turn, increases the need for increased
inspiratory activity (larger and faster rate) to re-clear the airways
and facilitate gas exchange. This suggestion is consistent with
the nding that infants born by CS and who develop TTN also
display increased grunting and expiratory braking.4 It is also not
surprising, therefore, that CPAP, which maintains a positive pres-
sure on the airways to oppose liquid re-entry into the airways, is
an effective treatment for TTN.
It is interesting that, compared with near term infants,
preterm infants do not appear to share the same risk of
increased respiratory morbidity (eg, TTN) when delivered by
CS as opposed to vaginal delivery. Perhaps, this reects the
structural immaturity of the preterm lung, whereby preterm
infants have lungs with relatively more interstitial tissue and
smaller gas exchange surface areas. A relatively larger interstitial
tissue compartment allows larger volumes of liquid to be accom-
modated with only small increases in pressure, whereas a
smaller surface area will restrict the bidirectional movement of
liquid across the epithelium. Indeed, a reduced distal airway
surface area will not only restrict airway liquid clearance, but
will also restrict liquid re-ooding back into the airways.
Logically, a reduced surface area will mainly affect airway
re-ooding due to the lower transepithelial pressure gradients
driving liquid movement in that direction. As such, it is possible
that preterm infants can cope with both higher liquid volumes
and interstitial tissue pressures, without resulting in airway
re-ooding.
Liquid accumulation within lung tissue is likely to have conse-
quences other than an increased potential for liquid to re-enter
the distal airways. Indeed, it is likely to substantially alter tissue
mechanics, potentially making the lung signicantly less compli-
ant and thereby increasing the pressures required to inate it.
While this could also act as an inbuilt protective mechanism
that reduces the potential of overination-induced lung injury,
unequal distribution of this liquid within different regions will
greatly alter compliance differences across the lung. This may
contribute to inhomogeneous ventilation of the lung and
increasing the risk of overination injury in more compliant
lung regions, particularly non-dependent lung regions. To fully
comprehend the signicance of tissue liquid accumulation, it is
important to determine the extent to which accumulation
differs in different lung regions and whether the liquid is
mobile. That is, can it move between lung regions through the
tissue due to gravity-related pressure gradients that are known
to exist in the lung, for example, between dependent and non-
dependent lung regions?
PHASE 3: RESPIRATORY GAS EXCHANGE AND METABOLIC
HOMEOSTASIS
Following lung aeration and the clearance of liquid from the
tissue, the infant has passed through the immediate birth transi-
tion phase. While some fetal characteristics may persist (eg,
patent duct), the approaches used to assist lung function and
respiratory gas exchange at this time are more akin to the trad-
itional approaches that are commonly practised by caregivers in
neonatal intensive units. It is possible that pulmonary oedema
and increased interstitial tissue pressures may reoccur in
response to problems such as pulmonary hypertension.
Hooper SB, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1F6. doi:10.1136/archdischild-2013-305704
Review
However, in the absence of these morbidities, ventilation can be
more focused towards gas exchange and maintaining respiratory
gas homeostasis. In this situation, the success of establishing
adequate gas exchange will depend on overcoming the structural
and functional deciencies of the lung as well as the immaturity
of the respiratory muscles and the high compliance of the chest
wall. The mechanisms and approaches of this respiratory phase
have been extensively described previously and will not be dis-
cussed here. Instead, we suggest that the priorities of this phase
should not overly dominate the focus of respiratory support
provided to preterm infants as they transition to newborn life.
Indeed, the optimal management of preterm infants during the
early phases will include a variety of considerations in addition
to these traditional approaches.
SUMMARY
We propose that at birth the lung passes through three distinct,
but overlapping phases as it transitions into the primary gas
exchange organ at birth. As the physiological state of the lung
during each phase is distinctly different, we suggest that the
respiratory support given to infants should be optimised to suit
the lungs underlying physiological state during each phase.
During the rst phase, pulmonary gas exchange cannot occur as
the terminal airways are liquid-lled and so respiratory support
should be focused on clearing liquid from the gas exchange
regions. Due to the absence of gas exchange, little or no CO2
will accumulate within the airways and so the need to exhale
the CO2 is unnecessary. As such, it is logical to consider sustain-
ing the initial ination pressures to allow the lung to fully aerate
before being deated. However, we need to await the outcomes
of current clinical trials to assess the efcacy of this treatment in
humans. During the second phase, although the gas exchange
regions are mostly cleared of liquid, this liquid resides within
the perialveolar interstitial tissue, which increases hydrostatic
pressures and the risk of liquid re-entry back into the airways.
As a result, respiratory support should be optimised to minimise
alveolar re-ooding during expiration, which can be achieved by
applying an end-expiratory or continuous positive pressure. The
third and nal phase occurs when the liquid is eventually
cleared from lung tissue. Although gas exchange may be
restricted by lung immaturity, injury and inammation during
this phase, considerations of how fetal lung liquid can adversely
affect lung function has less relevance.
Contributors SBH wrote the initial draft, which was modied and edited by ABtP
and MJK.
Funding This research was supported by an NHMRC Program Grant (606789) and
the Victorian Governments Operational Infrastructure Support Program.
Competing interests SBH is supported by an NHMRC Principal Research
Fellowship, ABtP is supported by a Veni-grant from The Netherlands Organisation
for Health Research and Development (91612027). MJK is supported by an ARC
Australian Research Fellowship (grant DP110101941).
Provenance and peer review Commissioned; externally peer reviewed.
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Respiratory transition in the newborn: a

three-phase process
Stuart B Hooper, Arjan B te Pas and Marcus J Kitchen

Arch Dis Child Fetal Neonatal Ed published online November 5, 2015

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