Eur J Pediatr (2017) 176:1287–1293

DOI 10.1007/s00431-017-2984-y

REVIEW

Achieving and maintaining lung volume in the preterm infant:

from the first breath to the NICU
Gianluca Lista 1 & Andrés Maturana 2 & Fernando R. Moya 3

Received: 29 June 2017 / Revised: 24 July 2017 / Accepted: 3 August 2017 / Published online: 10 August 2017
# Springer-Verlag GmbH Germany 2017

Abstract The main goal for the neonatologist is to facili-
tate the adaptation to extra-uterine life during initial transi-
tion, while minimizing lung injury opening and protecting
the premature lung from the first breath onwards. An ap-
propriate management from birth should lead to the
achievement of an early functional residual capacity
(FRC), and the following steps should aim at maintaining
an adequate lung volume. To date, different strategies are
available to optimize fetal-neonatal transition and promote
lung recruitment. New ventilation approaches, such as
sustained lung inflation (SLI) and “open lung strategy”,
well-established ventilation techniques with a more tailored
application and less invasive modalities to administer sur-
factant have been recently introduced in clinical practice
with promising results.
Conclusions: given the current status of neonatal care, it
seems that lung injury and BPD could be reduced with multi-
ple strategies starting early in the delivery room. Literature
Communicated by Patrick Van Reempts
underlines the importance of a respiratory tailored manage-
ment of preterm infants from birth and during the whole
NICU stay.
What is Known:
• Experimental and clinical studies have shown that the transition from
fetal to adult type cardiorespiratory circulation needs an adequate
lung ventilation. An appropriate management in the delivery room
should lead to the achievement of an early FRC, and through the
following steps, the neonatologist should aim at maintaining an
adequate lung volume.
• Literature underlines the importance of a respiratory tailored
management of preterm infants during the whole NICU stay to
maintain the benefits of a successful postnatal adaption.
What is New:
• Herewith, we describe the most relevant and recent interventions which
can be performed from the delivery room to the NICU stay to
guarantee an adequate tradition to postnatal life and an effective
cardiorespiratory stability.
Keywords Fetal-neonatal transition . Ventilation strategies .
Preterm infants . Optimization of lung volume

* Gianluca Lista
gianluca.lista@asst-fbf-sacco.it Abbreviations
BPD bronchopulmonary dysplasia
Andrés Maturana CPAP continuous positive airway pressure
amaturana@udd.cl ELGAN extremely low gestational age neonate
Fernando R. Moya FRC functional residual capacity
fernando.moya@ccneo.net GA gestational age
HFNC high-flow nasal cannula
1
NICU “V. Buzzi” Children’s Hospital, ASST-FBF-Sacco, Via HFV high-frequency ventilation
Castelvetro, 32, 20154 Milan, Italy LISA less invasive surfactant administration
2
Division of Neonatology, Clínica Alemana, Santiago, Chile LRM lung recruitment maneuver
3
Coastal Carolina Neonatology, Coastal Children’s Services, PLLC, MIST minimally invasive surfactant therapy
Wilmington, NC 28401, USA MV mechanical ventilation
1288
N-CPAP nasal continuous positive airway pressure
NIPPV nasal intermittent positive pressure ventilation
PEEP positive end expiratory pressure
RDS respiratory distress syndrome
RFM respiratory function monitor
SI sustained inflation
SIMV synchronized intermittent mechanical ventilation
VILI ventilator-induced lung injury
VLBW very low birth weight
Introduction
The preterm infant is born with a fluid-filled and immature
lung. Therefore, facilitating the adaptation to extra-uterine life
during that initial transition, while minimizing lung injury,
continues to be an enormous challenge for the neonatologist
[59]. Antenatal steroid prophylaxis and surfactant replacement
therapy have effectively reduced the incidence and severity of
respiratory distress syndrome (RDS) in preterm infants [44].
Nevertheless, bronchopulmonary dysplasia (BPD) still re-
mains one of the most common respiratory complications in
very low birth weight (VLBW) infants [8]. Barotrauma,
volutrauma, and oxygen toxicity trigger an inflammatory re-
sponse in the immature lung, which is an important mecha-
nism contributing to BPD, among others [1]. Tailoring the
initial lung expansion maneuvers and ventilatory strategies
to the patient’s underlying physiology seem essential in order
to minimize “ventilator-induced lung injury” (VILI) [51]. In
this review, we have tried to discuss both the physiologic
mechanisms that challenge establishing adequate lung volume
and the different lung recruitment strategies studied thus far,
which might be incorporated during the initial respiratory
management of the preterm infant.
Delivery room lung recruitment
The preterm neonate, particularly that of an extremely low
gestational age (ELGAN), often has limitations in achieving
and maintaining “adequate” lung volume due primarily to a
quantitative and qualitative surfactant deficiency coupled with
a poor respiratory effort [23]. These two “respiratory handi-
caps” are mostly responsible for the respiratory failure that
affects, with variable severity, about 60–70% of infants born
before 28 weeks’ gestation and a smaller proportion of those
above that GA.
In the physiologic transition from intra to extra-uterine life,
aeration of the fetal lung and clearance of fetal lung liquid
from the alveoli are very important steps during initial adap-
tation of the newborn [37]. The initiation of rhythmic pulmo-
nary respirations, the increase in oxygen tension in the pulmo-
nary vasculature, and the reduction of arterial pulmonary
Eur J Pediatr (2017) 176:1287–1293
pressure, all play an important role in the cascade of events
triggered by the first breaths [37]. This transition leads to the
transformation from a fetal to a neonatal pattern of circulation
that is characterized by the opening and integration of the
pulmonary vasculature and a progressive separation of right
and left heart function [37]. Moreover, the fetal ventricle is
very stiff and, as in adults, the dimensions of the fetal heart are
significantly influenced by the constraint of the surrounding
tissues (rib cage, lungs, and pericardium) [19].
In fetal life, the fluid-filled lungs as well as the amniotic
fluid and surrounding maternal tissues probably contribute to
this constraint. It is controversial as to what extent lung fluid
clearance begins during fetal life [20]. At birth, the aeration of
the lungs, together with the relief of the constraint imposed by
the amniotic fluid and maternal tissues, may also contribute to
an increase in cardiac output [16, 27]. The mechanism of lung
fluid reabsorption and lung aeration at birth, initially attributed
only to the epithelial channel function, has been recently
linked to changes in transpulmonary pressure that follow the
first breaths [21]. The contribution of Beta adrenergic stimu-
lation and vasopressin-mediated activation of epithelial sodi-
um channels cannot solely explain the rate of fluid clearance
observed at birth in healthy newborns [39, 57]. In fact, the
term infant after delivery presents a particular respiratory pat-
tern characterized by 4–5 “prolonged “breaths (4–5 s’ duration
each), which generates a large tidal volume. This in turn cre-
ates an early functional residual capacity (FRC) by replacing
the fluids from the lung with gas [25, 49]. In animal studies, it
has been demonstrated that the difference in pressure during
inspiration is the main determinant of the fluid removal from
the lung [50]. The fluid is eventually reabsorbed via sodium
channel activation and eventually goes to the lymphatic and
venous vessels [22, 39]. Lung volume, once generated, is
maintained without a continuous opening and closing of the
alveoli (responsible for the biotrauma), if the surface tension is
reduced by adequate surfactant function and positive end ex-
piratory pressure (PEEP) that opposes the collapse of the al-
veoli [20].
In a preterm infant, lung volume optimization from the first
breath should allow a more physiological transition from fetal
to neonatal life while maintaining adequate gas exchange and
preventing or limiting lung injury. A prolonged inflation
(sustained inflation or SI) in a fluid-filled lung followed by
adequate PEEP has been successfully used to recruit the lung
in the early transitional phase to extra-uterine life in preterm
animal models [40]. The SI maneuver seems a reasonable
approach to allow premature infants to achieve an FRC rap-
idly. Reports of prompt increases in heart rate as well as cere-
bral and systemic oxygenation in preterm infants exposed to
SI in the delivery room are signs suggestive of a positive effect
of this maneuver [16]. Some clinical trials have shown the
feasibility of using a SI of 20–25 cm H2O for 10–20 s in
preterm infants at risk for RDS or with signs of early
Eur J Pediatr (2017) 176:1287–1293
respiratory failure [48]. Two recent meta-analyses concluded
that SI applied by mask or pharyngeal tube in preterm infants
at risk for respiratory failure reduces the need for endotracheal
intubation and mechanical ventilation within the first 72 h
after birth albeit with no impact on death or BPD [38, 48].
These studies were not very large and also varied in terms of
the SI maneuvers utilized. This notwithstanding, the most re-
cent resuscitation guidelines argue “against the routine use of
initial SI (greater than 5 seconds duration) for preterm infants
without spontaneous respiration immediately after birth but an
SI may be considered in individual clinical circumstances or
research settings” [47]. An ongoing international multicenter
trial (SAIL trial) will compare an initial SI with PEEP to initial
positive pressure ventilation with PEEP in extremely preterm
infants (23+0–26+6 weeks GA) requiring resuscitation/respira-
tory intervention, in order to determine the efficacy of this
intervention in preventing BPD or death [14].
In a recent systematic review, the initial use of nasal CPAP
(thereby providing PEEP) was demonstrated to be beneficial
when compared to endotracheal intubation and mechanical
ventilation (MV) in very preterm infants by reducing the need
for MVand surfactant, plus decreasing BPD and the combined
outcome of death or BPD [52]. However, there was insuffi-
cient data to compare prophylactic nasal CPAP to other forms
of oxygen administration or supportive care [52].
Nevertheless, the use of prophylactic nasal CPAP is currently
recommended in the initial respiratory management of the
preterm infant [61]. Recent data using a preterm lamb model
have shown that a stepwise PEEP strategy at birth emphasiz-
ing time- and pressure-based recruitment and titrated to the
subject’s lung mechanics was practical and demonstrated
short-term beneficial results [55]. An observational study de-
scribing delivery room management with stepwise increments
of PEEP (e.g., from 8 to 14 cm H2O if necessary) plus surfac-
tant administration was shown to improve the rates of survival
and morbidity, and reduce the need for mechanical ventilation
among infants < 26 weeks GA [33]. However, this was a
bundled approach that included other interventions that may
have impacted outcomes. Thus, it needs to be tested in a ran-
domized trial before gaining wide acceptance.
When preterm infants need respiratory assistance in the
delivery room, respiratory function monitoring (RFM) is de-
sirable to deliver adequate and gentle resuscitation maneuvers
and to identify potential pitfalls during mask ventilation [31].
However, establishing this approach may be technically
challenging.
After a preterm infant has cleared the liquid from his/her
lungs, gas exchange becomes possible in the recruited alveoli.
This liquid initially remains in the surrounding interstitial tis-
sues with a great risk of re-entering the alveoli and interfering
with gas exchange [22]. Maintaining a constant distending
pressure in the airway using CPAP is important in this early
phase to avoid losing the acquired FRC [40]. Therefore,
1289
transport from the delivery room to the NICU must guarantee
a reliable administration of PEEP in the recently recruited
lung.
Maintaining and optimizing lung volume
in the NICU
When the infant requires only a non-invasive respiratory ap-
proach, it seems reasonable to aim for an optimal level of
continuous distending pressure to maintain CO2 within the
desired target and an adequate saturation with minimal FiO2.
Nonetheless, despite optimal management in the delivery
room, almost half of VLBW infants initially placed on nasal
CPAP require mechanical ventilation and therefore are at fur-
ther risk for VILI [2, 60].
Lachman legitimized the relevance of opening the lung in
mechanically ventilated patients using adequate positive in-
spiratory pressure and later keeping it open with PEEP [29].
Several animal studies have validated the relevance of an
“open lung” strategy for minimizing lung injury [32, 34,
43]. To reduce VILI in ventilated premature infants, we must,
at least in theory, aim to ventilate a recruited or “open lung”
with an adequate tidal volume (Vt) [26]. The target is to set the
lung volume on the deflation limb of the pressure/volume (P/
V) curve and above the lower inflection point. A simple and
effective lung protective strategy is using PEEP and finding
the optimum level for each patient [35]. The use of a PEEP
level higher than the lower inflection point might result in an
excessively high PEEP with the risk of reaching the upper
inflection point with lung over distension [11, 43].
The “open lung” strategy also applies to volume-targeted
ventilation, whose beneficial effects can be achieved with an
even distribution of the tidal volume throughout the lungs
[26]. On the other hand, the strain and stress forces acting in
areas of the lung, where an inflated zone is adjacent to a
collapsed or fluid-filled zone (border zone), may lead to a
pronounced interstitial edema due to interdependence with
an increased transpulmonary pressure [11, 15]. In a small con-
trolled trial Castoldi and colleagues compared infants,
< 27 weeks gestational age with RDS ventilated on assist
control plus volume guarantee with and without a lung recruit-
ment maneuver (LRM) after surfactant administration within
the first 2 h of life [5]. Starting with a PEEP of 5 cm H2O,
repeated increments of 0.2 cm H2O of PEEP every 5 min
while monitoring the FiO2 requirements and arterial saturation
(SpO2) levels were applied. PEEP was increased progressive-
ly if a fall of FiO2 requirements and increase of the SpO2 were
noted. When an FiO2 of 0.25 was reached, a slow stepwise
PEEP reduction was started while monitoring the SpO2 levels.
When oxygenation levels fell and FiO2 administration rose
consequently, PEEP was increased until stable oxygenation
was achieved, and the FiO2 level reached the level prior to
1290
the fall in oxygenation. No adverse effects were described
during the maneuver, and the LRM group showed a faster
reduction in FiO2 and a shorter oxygen dependency [5].
These preliminary results suggest that the open lung concept
is a reasonable practice to add to volume-targeted ventilation
in premature infants with RDS.
When using pressure-targeted ventilation, the physician
should also control the resulting Vt by continuously adjusting
the differential pressure to try limiting VILI. During the
weaning phase when using synchronized intermittent manda-
tory ventilation (SIMV), it is important to avoid long periods
of spontaneous breathing in endotracheal CPAP that could
result in lung derecruitment and increased work of breathing.
This can be achieved by adding pressure support to SIMV
[46].
Surfactant as a recruitment maneuver
Lung maturation is not complete generally until at least 35 to
36 weeks of gestational age [17]. Endogenous surfactant is
necessary for adequate lung function, and most surfactant de-
ficient infants will develop RDS [24]. On the contrary, many
premature infants may not require exogenous surfactant be-
cause of early maturation and/or optimization of existing sur-
factant pools by antenatal steroid exposure and early CPAP
[23]. Exogenous surfactant can also have a role in the initial
transition to extra-uterine life in surfactant deficient infants.
The timing of exogenous surfactant has shifted from a pro-
phylactic approach to an early selective administration proba-
bly due to a widespread use of antenatal steroids and early
nasal CPAP [45]. Although early surfactant seems more effec-
tive than delayed administration [3], it remains a difficult clin-
ical decision which patients and when should receive early
exogenous surfactant, especially because at present, surfactant
administration implies mostly the use of endotracheal intuba-
tion with a regular endotracheal tube or various other ap-
proaches to gain access to the lower airway. Although very
few studies have included infants below 25–26 weeks of ges-
tation, most of those extremely premature infants will require
intubation and surfactant administration [12, 23]. Considering
that most studies have shown that the majority of infants at 23
and 24 weeks require intubation, one could venture to say that
at this age, prophylactic or very early surfactant could have a
role by helping to achieve an adequate FRC in the delivery
room or shortly thereafter [12, 28]. Surfactant deficient lungs
show decreased compliance, no hysteresis, low residual, and
total lung volumes [56]. Therefore, surfactant administration
can be considered a very efficient recruiting strategy. It has
been shown that FRC increases significantly after surfactant
therapy in premature infants [18], even before an improve-
ment in oxygenation is observed. Traditionally, surfactant ad-
ministration has implied endotracheal intubation, which very
Eur J Pediatr (2017) 176:1287–1293
frequently is followed by prolonged MV or, alternatively, an
attempt for rapid extubation to CPAP, the so-called INSURE
procedure [41]. Intubating an infant is an invasive maneuver,
which may also be potentially harmful, so less or minimally
invasive methods (less invasive surfactant administration,
LISA; or, minimally invasive surfactant treatment, MIST)
for surfactant administration are being evaluated and are
gaining increasing acceptance [36]. In the course of the
LISA/MIST procedure [7, 28], surfactant is delivered
intratracheally without traditional intubation and bagging,
but rather using a fine catheter inserted into the trachea of
spontaneously breathing preterm infants while on N-CPAP.
By avoiding mechanical ventilation and manual inflations, it
is possible that this approach might reduce lung injury due to
baro-volutrauma as well as BPD [13]. Moreover, leaving the
infants supported by N-CPAP during the maneuver should
reduce the risk of lung derecruitment. The not too distant
future may provide us with the possibility of maintaining an
infant in nasal CPAP while administering surfactant in aero-
solized form. This is currently undergoing clinical testing
[42].
Lung volume optimization during high-frequency
ventilation
High-frequency ventilation (HFV) has proven to be at least
comparable to conventional ventilation in terms of the inci-
dence of BPD and other outcomes [6, 62]. During HFV, the
high lung volume strategy has become routine practice, using
a progressive increase of the continuous distending pressure to
reduce the need of FiO2 by SpO2 target monitoring [10]. Once
the desired lung volume is achieved, the mean airway pressure
can be progressively reduced to set the lung volume on the
deflation limb of the P/V curve guided by SpO2 monitoring
[10]. This strategy of ventilatory support is a very efficient
way of recruiting the lung while minimizing variations in lung
volume and, therefore, making this approach lung protective
[54].
Other considerations
Adequately, opening the preterm lung is challenging, and pro-
cedures that can potentially de-recruit the lung should be
avoided or minimized. Any procedure that requires opening
the ventilatory circuit implies losing pressure and therefore
potentially losing FRC [4]. The introduction of a negative
pressure in the airway during suctioning can also have a neg-
ative impact on lung recruitment. A closed suctioning system
is preferable but will not eliminate the impact of airway
suctioning during mechanical ventilation [53]. Therefore, in
Eur J Pediatr (2017) 176:1287–1293
the ventilated infant, suctioning should probably be done only
when there are secretions present.
Finally, the choice of non-invasive respiratory support after
extubation should be tailored to the underlying respiratory
disease and also needs to consider the gestational age of the
infant. The available devices and the experience of the nursing
team with each alternative should also be taken into consider-
ation. Various studies in VLBW infants have demonstrated the
efficacy of N-CPAP in the post-extubation phase following
mechanical ventilation instead of direct extubation, probably
due to the capacity of CPAP to maintain lung volume [9].
Nevertheless, sometimes CPAP fails after extubation and neo-
natologists use as an alternative nasal intermittent positive
pressure ventilation (NIPPV). A recent meta-analysis com-
pared management of preterm infants with N-CPAP versus
NIPPV after extubation [30]. The Cochrane review concluded
that NIPPV reduces the incidence of extubation failure and the
need for re-intubation within 48 h to 1 week more effectively
than N-CPAP. Recently, there is a great interest around the use
of high-flow nasal cannulae (HFNC) in the post-extubation
phase. A recent meta-analysis demonstrated that HFNC has
similar rates of efficacy to other forms of non-invasive respi-
ratory support in preterm infants to prevent failure of
extubation [58]. Therefore, HFNC may be considered a valid
alternative to N-CPAP in this phase of the management of
preterm infants with RDS.
Conclusions
We have tried to review the various alternatives for opening
and protecting the premature lung from the first breath on-
wards. It is improbable that a single strategy will be able to
significantly impact lung injury and BPD in preterm infants
given the current status of neonatal care. Nevertheless, we
believe that close attention to achieving and maintaining an
appropriate lung volume using various strategies throughout
the respiratory management of preterm infants could poten-
tially make a difference in lung injury and thereby reduce the
risk of BPD.
Authors’ contributions Dr. Gianluca Lista conceptualized this paper,
drafted the initial manuscript, and revised the final version. Dr. Andres
Maturana conceptualized this paper and reviewed the manuscript. Dr.
Fernando Moya conceptualized the paper and wrote the final manuscript.
All authors agree with the final paper as submitted.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
1291
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