children

Review
The Respiratory Management of the Extreme Preterm in the
Delivery Room
Raquel Escrig-Fernández 1, * , Gonzalo Zeballos-Sarrato 2 , María Gormaz-Moreno 1 , Alejandro Avila-Alvarez 3 ,
Juan Diego Toledo-Parreño 1 and Máximo Vento 1

1 Department of Neonatology, Hospital Universitari i Politècnic La Fe, 106 Fernando Abril Martorell Avenue,
46026 Valencia, Spain
2 Department of Neonatology, Hospital Gregorio Marañón, 28009 Madrid, Spain
3 Division of Neonatology, Pediatric Department, Complexo Hospitalario Universitario de A Coruña (CHUAC),
Sergas, 15006 A Coruña, Spain
* Correspondence: [email protected]

Abstract: The fetal-to-neonatal transition poses an extraordinary challenge for extremely low birth
weight (ELBW) infants, and postnatal stabilization in the delivery room (DR) remains challenging.
The initiation of air respiration and the establishment of a functional residual capacity are essential
and often require ventilatory support and oxygen supplementation. In recent years, there has been
a tendency towards the soft-landing strategy and, subsequently, non-invasive positive pressure
ventilation has been generally recommended by international guidelines as the first option for
stabilizing ELBW in the delivery room. On the other hand, supplementation with oxygen is another
cornerstone of the postnatal stabilization of ELBW infants. To date, the conundrum concerning
the optimal initial inspired fraction of oxygen, target saturations in the first golden minutes, and
oxygen titration to achieve desired stability saturation and heart rate values has not yet been solved.
Moreover, the retardation of cord clamping together with the initiation of ventilation with the patent
cord (physiologic-based cord clamping) have added additional complexity to this puzzle. In the
Citation: Escrig-Fernández, R.;
present review, we critically address these relevant topics related to fetal-to-neonatal transitional
Zeballos-Sarrato, G.; Gormaz- respiratory physiology, ventilatory stabilization, and oxygenation of ELBW infants in the delivery
Moreno, M.; Avila-Alvarez, A.; room based on current evidence and the most recent guidelines for newborn stabilization.
Toledo-Parreño, J.D.; Vento, M. The
Respiratory Management of the Keywords: prematurity; fetal-to-neonatal transition; non-invasive ventilation; oxygenation;
Extreme Preterm in the Delivery micropreemie
Room. Children 2023, 10, 351.
https://doi.org/10.3390/
children10020351

Academic Editors: Shmuel Arnon

1. Introduction
and Bernhard Schwaberger A successful fetal-to-neonatal transition relies on a series of exquisitely orchestrated
physiological events that enable the switch from the placental intervillous gas exchange to
Received: 12 December 2022
lung air respiration [1]. The initiation of breathing movements immediately after birth in
Revised: 3 February 2023
Accepted: 6 February 2023
term infants is characterized by deep inspiratory diaphragmatic, intercostal, and subcostal
Published: 10 February 2023
muscular contractions that cause a tridimensional expansion of the thoracic cage. Thorax
expansion contributes to the creation of a negative transthoracic pressure equal to or greater
than −40 cmH2 O. This is the driving force that will facilitate the extrusion of the fluid
filling the conductive airways into the alveolar interstitial space. Lung aeration permits
Copyright: © 2023 by the authors. alveolar gas exchange, which subsequently causes a sudden increment of arterial partial
Licensee MDPI, Basel, Switzerland. pressure of oxygen (PaO2 ) [2–4].
This article is an open access article Oxygen is a potent vasodilator that contributes to pulmonary arterial vessel dilata-
distributed under the terms and tion, thus reducing pulmonary vascular resistance [5]. Consequently, there is a significant
conditions of the Creative Commons increase in pulmonary blood flow from 138 to 245 mL/kg/min [1]. In addition, increased
Attribution (CC BY) license (https:// PaO2 favors the closure of the ductus arteriosus [1]. Moreover, enhanced preload of both
creativecommons.org/licenses/by/ the right and the left ventricles will mechanically contribute to the closure of the foramen
4.0/).

Children 2023, 10, 351. https://doi.org/10.3390/children10020351 https://www.mdpi.com/journal/children

Children 2023, 10, 351 2 of 21

ovale. Thus, in several minutes, the newborn infant switches from a serial to a parallel type
of circulation that will persist throughout their entire life [1].
In term newborns, birth asphyxia is the most common condition needing resusci-
tation [6]. The main intervention under these circumstances will be to provide positive
pressure ventilation to restore an effective gas exchange and to supply oxygen and glucose
to the central nervous system and myocardium, both of which are essential for the infant’s
survival [7]. However, preterm infants who represent approximately 10% of all deliveries
worldwide are especially predisposed to difficulties in establishing a regular and effective
pattern of respiration immediately after birth. The immaturity of the respiratory drive
and lung cytoarchitecture, the lack of surfactant production, the excessive elasticity of the
thoracic cage, and the debility of the respiratory musculature often hamper the initiation of
the first inspiratory movements, the establishment of an effective clearance of lung fluid,
and the establishment of a functional residual capacity (FRC). All these circumstances
frequently lead preterm infants, especially very preterm infants, to respiratory insufficiency.
Consequently, a substantial proportion of preterm infants will need respiratory support in
the first minutes after birth including oxygen supplementation to satisfactorily undergo
postnatal stabilization [8].
Only a decade ago, preterm babies needing respiratory support in the first minutes
after birth were directly intubated and ventilated [9]. However, the concept of “the first
golden minutes” was put forward, aiming to achieve postnatal stabilization by employing
the least aggressive approach in babies who were mostly spontaneously breathing and cry-
ing and just needed some support to overcome the difficulties inherent to their immaturity.
This concept was primarily targeted toward ventilation upon stabilization in the delivery
room (DR) [10].
In recent years, delaying cord clamping has become a standard of care in term and
preterm infants [11,12]. Evolving pulse oximeter saturation and heart rate (HR) in the first
10 min after birth in healthy term babies with delayed cord clamping significantly differs
from Dawson’s nomogram, which constitutes the reference range for the management of
oxygen in the DR [13,14]. Initiating ventilation with a patent cord has implied physiological
advantages in the experimental setting [15]. This new approach to positive pressure
ventilation in the DR is being explored by different research groups [16–20]; however,
results are not yet available, therefore caution in the application of this new modality of
ventilation should guide our steps and be restricted to randomized controlled trials (RCTs).
Positive pressure ventilation (PPV) in the DR is of paramount importance for the resus-
citation of term and the stabilization of preterm infants immediately after birth. The present
review article provides a critical update to the recently published experience of ventilation
in the DR of extreme preterm defined as newborn infants born at <28 weeks gestation.

2. Physiology of the Respiratory Fetal-to-Neonatal Transition

During fetal life, the gas exchange between mother and fetus takes place in the inter-
villous spaces of the placenta. Increased pulmonary vascular resistance renders pulmonary
blood flow almost inexistent. Hence, oxygenated blood is redirected through fetal shunts
(ductus venosus, foramen ovale, and ductus arteriosus) to the upper part of the body and
especially to the cerebral and coronary circulations, thus avoiding non-perfused lungs
that are not responsible for the fetal gas exchange [21]. Hence, oxygenated blood from
the placenta is only partially merged with deoxygenated blood from the fetal superior
vena cava.
At birth, physiological factors such as the interruption of cord blood flow and the
initiation of inspiratory efforts will cause significant hemodynamic changes. A sudden
increase in the systemic vascular resistance caused by the interruption of the umbilical
arteries’ blood flow contributes to the inversion of flow in the ductus arteriosus and
foramen ovale causing their functional and anatomical closure. Simultaneously, the first
inspiratory efforts extrude liquid filling the lungs, favor surfactant distribution, prompt
lung aeration, and establish an FRC, which triggers a decrease in pulmonary vascular
 foramen ovale causing their functional and anatomical closure. Simultaneously, the first
inspiratory efforts extrude liquid filling the lungs, favor surfactant distribution, prompt
Children 2023, 10, 351 3 of 21
lung aeration, and establish an FRC, which triggers a decrease in pulmonary vascular re-
sistance, increases the pulmonary blood flow and oxygenation, and reduces the work of
breathing. The establishment of an FRC is the cornerstone of the postnatal adaptation of
resistance,
the newly bornincreases the pulmonary blood flow and oxygenation, and reduces the work of
infant.
breathing. The establishment
Subsequently, the left heartof an FRC iswith
preload the oxygenated
cornerstone blood
of the increases
postnatal and
adaptation
closes theof
the newly
septal born
layer infant.
of the foramen ovale. Hence, the sudden postnatal increase in pulmonary
bloodSubsequently,
flow directly the left heart
depends preload
on lung withand
aeration oxygenated
oxygenationblood increases
and and to
is essential closes the
prevent
septal layer of the foramen ovale. Hence, the sudden postnatal increase
the drop in cardiac output that will occur if cord clamping precedes lung aeration [21]. in pulmonary
bloodThe
flow directly depends
fetal-to-neonatal on lung establishes
transition aeration and oxygenationcirculation
parallel-type and is essential
in whichto prevent
deoxy-
the drop blood
genated in cardiac output
reaches the that
rightwill occur
heart andifiscord clamping
directed precedes lungpulmonary
to low-resistance aeration [21].
circu-
lationThe fetal-to-neonatal
where oxygenation transition
takes place. establishes parallel-type
By contrast, circulation
the full return in which deoxy-
of oxygenated blood
genated
from theblood
lungsreaches
to the the
leftright
heartheart and is directed
is directed to low-resistance
to systemic circulation topulmonary circulation
provide tissue oxy-
where oxygenation
genation [21]. takes place. By contrast, the full return of oxygenated blood from the
lungsThere
to theareleftaheart
numberis directed
of reasonsto systemic
why the circulation
physiologicalto provide tissue oxygenation
fetal-to-neonatal transition[21].
can
be disrupted in preterm infants [21–23]: Surfactant deficit, weaker respiratory drive,can
There are a number of reasons why the physiological fetal-to-neonatal transition be
peri-
disrupted in preterm infants [21–23]: Surfactant deficit, weaker respiratory
odic respiration or even apneic episodes, low inherent cardiac contractility, limited ability drive, periodic
respiration or even
to adjust cardiac apneicpoorer
output, episodes, low inherent
tolerance cardiac contractility,
to high systemic limited ability
vascular resistance, and per- to
adjust cardiac output, poorer tolerance to high systemic vascular resistance,
sistence of fetal shunts. In this context, respiratory support in the delivery room may be and persistence
of fetal shunts. In this context, respiratory support in the delivery room may be the key to a
the key to a successful or failed transition and, finally, to better or worse clinical outcomes.
successful or failed transition and, finally, to better or worse clinical outcomes.
Figure 1 summarizes the alveolar changes in the fetal-to-neonatal transition. In pre-
Figure 1 summarizes the alveolar changes in the fetal-to-neonatal transition. In preterm
term infants, although crying and spontaneous breathing is often present, the respiratory
infants, although crying and spontaneous breathing is often present, the respiratory effort
effort can be weaker than necessary to establish an FRC. Under these circumstances, the
can be weaker than necessary to establish an FRC. Under these circumstances, the applica-
application of positive airway pressure will contribute to the generation of a sufficient
tion of positive airway pressure will contribute to the generation of a sufficient pressure
pressure gradient to extrude the fluid in the lung to the interstitial space. In addition, pre-
gradient to extrude the fluid in the lung to the interstitial space. In addition, preterm infants
term infants have delayed clearance of lung fluid because of decreased sodium resorption
have delayed clearance of lung fluid because of decreased sodium resorption and weaker
and weaker respiratory drive [24,25]. Either a large pressure gradient (inflating pressure)
respiratory drive [24,25]. Either a large pressure gradient (inflating pressure) or a greater
or a greater duration of inflation may be needed [26].
duration of inflation may be needed [26].

Figure
Figure 1.1. In
In fetal
fetallife,
life,lung
lungand
andrespiratory airways
respiratory areare
airways filled withwith
filled fluidfluid
(panel (A)).(A)).
(panel Immediately after
Immediately
birth, intense respiratory efforts generating intense pressures extrude lung fluid to
after birth, intense respiratory efforts generating intense pressures extrude lung fluid to the inter- the interstitium,
and closure
stitium, of the glottis
and closure and surfactant
of the glottis distribution
and surfactant in theinsurface
distribution of the
the surface alveoli
of the contributes
alveoli contributesto
establishing
to establishing a functional
a functional residual
residualcapacity
capacity(panel
(panel(B)).
(B)).Ongoing
Ongoingrespiratory
respiratoryefforts
efforts once
once the
the FRC
has been established require less positive positive inspiratory pressures (PIP) and and positive-end
positive-end expiratory
pressures (PEEP)
pressures (PEEP) to to maintain
maintain anan adequate
adequate gas
gas exchange
exchange (panel
(panel (C)).
(C)).

Of note, fluid accumulated in the alveolar interstitium generates positive pressure

against the alveoli, which translates into an increased tendency of alveolar collapse and
re-introduction of fluid within the alveoli during the expiratory phase. These circumstances
are aggravated by a lack of surfactants in premature infants. Therefore, a positive end
expiratory pressure (PEEP) or a continuous positive airway pressure (CPAP) has to be
Children 2023, 10, 351 4 of 21

applied as respiratory support to premature newborn infants to prevent lung edema and/or
atelectasis and alveolar collapse [26].
During fetal life, the larynx offers resistance to the efflux of lung liquid and, in contrast
to postnatal life, when apnea occurs in the fetus, the glottis remains closed in an attempt to
prevent the loss of intrapulmonary fluid that is essential for fetal lung growth [27]. Recent
imaging studies in a rabbit model have shown that the onset of spontaneous breathing may
be the key step for this reflex to change and, therefore, for the glottis to remain open. Hence,
when ventilation fails in an apneic newborn infant, an airway obstruction secondary to a
persistence of the fetal glottis reflex may be the cause. In this situation, the focus should
be shifted toward stimulating breathing and avoiding the cause of apnea by standard
maneuvers such as cutaneous stimulation or rubbing the back [27].

3. Oxygen Supplementation in the Delivery Room

3.1. Oxygen in the Fetal-to-Neonatal Transition
The initiation of breathing immediately after birth boosts the availability of oxy-
gen in the newly born infant. The PaO2 rises from 30–40 mmHg (4–5.3 kPa) in utero to
70–80 mmHg (9.3–10.6 kPa) ex utero in a few minutes. Oxygen saturation, which fluctuates
from 45–55% in the fetus, rapidly increases to 85–95% in the first 10 min after birth [28]. It
is vital for the survival of very preterm infants (<32 weeks of gestation) to rapidly achieve
optimal oxygenation in the first minutes after birth when the energy demands exponentially
increase and gas exchange through the placenta is interrupted. As shown in Figure 2, a
careful balance in postnatal oxygenation is necessary because oxygen in excess causes
oxidative stress and harms cellular structures. On the other hand, postnatal hypoxemia is
associated with increased mortality and/or intra-peri-ventricular hemorrhage (IPVH) [29].
Current guidelines recommend preductal oxygen saturation (SpO2 ) monitoring with
a pulse oximeter and keeping SpO2 within recommended ranges after birth titrating FiO2
accordingly [7,30]. SpO2 targets for the first 10 min after birth were based on the percentiles
reference range put forward by Dawson JA et al. [13]. Dawson’s reference range was built
by merging three databases of newborn infants who did not need resuscitation in the
delivery room (DR). Only 30% of these babies were preterm and most of them were late
preterm [13]. Resuscitation guidelines (4) generally use the 25th percentile of Dawson’s
nomogram as a reference for SpO2 as the lower acceptable value. SpO2 considered “safe”
evolves from levels >60–65% in 2 min to >80% in 5 min [7,31]. The recommendation of
delaying cord clamping in recent guidelines [7] changed the reference range values for HR
and SpO2 in the first 10 min after birth. Ashish KC et al. [32] randomized 1510 women
with fetal HR ≥ 100 ≤ 160 bpm and gestational age (GA) ≥ 33 weeks to cord clamping
≤60 s and ≥180 s after birth. SpO2 was 18% higher by 1 min, 13% higher by <5 min, and
10% higher by 10 min in babies in the group of prolonged cord clamping. Padilla et al. [14]
built SpO2 and HR curves in healthy-term newborns with delayed cord clamping for a
median of 111 s. Compared with Dawson’s curves, they found significantly higher SpO2
and HR already in the first minute after birth. Thus, the median and IQR of SpO2 (%)
at 1, 5, and 10 min after birth were 77 (68–85), 94 (90–96), and 96 (93–98), respectively.
HR (beats per minute) median and IQR at 1, 5, and 10 min after birth were 148 (84–170),
155 (143–167), and 151 (142–161). Badurdeen et al. [16] stabilized preterm infants using
physiologically based cord clamping (PBCC). PBCC is defined as clamping the cord after
establishing lung aeration. Preterm infants at ≥32 + 0 weeks GA were randomized to either
early cord clamping (ECC) or PBCC either using PPV or effective spontaneous breathing
prior to cord clamping. The median GA for both groups was approximately 39 weeks GA.
Cord clamping was performed at a median of 136 s in the PBCC group and 37 s in the
ECC group. No differences in HR between 1 and 2 min after birth were evidenced. The
percentile chart for SpO2 was elaborated with a total of 295 infants >35 weeks GA with
delayed cord clamping ≥ 2 min. Out of these, 54.6% were born vaginally and 45.4% by
C-section. The median SpO2 reached 85% at 4 min and 90% at 5 min.
Children 2023, 10, x FOR PEER REVIEW 5 of 23
Children 2023, 10, 351 5 of 21

Figure
Figure 2. Fetal-to-neonatal
2. Fetal-to-neonatal transition
transition implies
implies a drastic
a drastic change
change to oxygen
to the the oxygen provided
provided to the
to the tissue
tissue
causing
causing physiologic
physiologic oxidative
oxidative stress.
stress. However,
However, under
under pathological
pathological circumstances,ananexcess
circumstances, excessofofoxy-
oxygen
gen can
canlead
leadtotohyperoxia
hyperoxiaand
andsubsequent
subsequent pathologic
pathologicoxidative stress
oxidative andand
stress tissue damage
tissue withwith
damage longlong
and/or
and/or short-term
short-term consequences.
consequences. In In contrast,
contrast, low
low oxygenationcan
oxygenation cancause
causehypoxemia,
hypoxemia,bradycardia,
bradycardia,and
andconsequently
consequentlyserious
seriouscomplications
complicationssuch
suchasas intra-peri-ventricular
intra-peri-ventricular hemorrhage
hemorrhage (IPVH)
(IPVH) and/or
and/or death.
death.
3.2. What Initial FiO2 Is Best for Very Preterm Infants in the First Minutes after Birth?
Current guidelines review
In a systematic recommend preductal oxygen
and meta-analysis, saturation
Saugstad (SpO
et cols. [33]2) showed
monitoring thatwith
the use
a pulse oximeter
of room air asand keeping with
compared SpO2 100%withinoxygen
recommended ranges after birth
for the resuscitation titrating FiOterm
of asphyxiated 2

accordingly [7,30]. SpOreduced

infants significantly 2 targets mortality.
for the first The102010
mininternational
after birth were based onguidelines
resuscitation the percen- were
tilesmodified
referenceand range
roomputair
forward by Dawson JA
was recommended as et
theal.initial
[13]. Dawson’s reference range
FiO2 for asphyxiated termwasinfants
built by merging
needing three databases
resuscitation [34–36].of newborn infants who did not need resuscitation in the
deliveryConcomitantly,
room (DR). Only 30% ofofthese
a series clinicalbabies were
studies preterm andinmost
summarized Tableof1 them were the
compared lateuse
preterm [13]. vs.
of higher Resuscitation
lower initialguidelines
FiO2 levels (4) during
generallytheuse the 25th percentile
stabilization of preterm of infants
Dawson’s in the
deliveryasroom.
nomogram The results
a reference for SpO of2 as
these
the studies concludedvalue.
lower acceptable that itSpOwas feasible to“safe”
2 considered stabilize
very from
evolves preterm infants
levels with in
>60–65% a lower
2 min(<0.3)to >80%initial
in 5FiO 2 . In
min addition,
[7,31]. the use of lower initial
The recommendation of
FiO
delaying reduced oxidative stress and inflammation as reflected
2 cord clamping in recent guidelines [7] changed the reference range values forby specific biomarkers [37,38].
HRHowever,
and SpO2 in preterm infants
the first 10 in thebirth.
min after lowerAshish
FiO2 group,
KC et al. the[32]
achievement
randomized of target saturation
1510 women
with was often
fetal ≥ 100 ≤ 160
HRdelayed andbpmtherefore these babiesage
and gestational needed
(GA)an ≥ 33increase
weeks in tothe
cord inspired
clamping ≤60 of
fraction
and ≥180Insec
sec oxygen. 2015, thebirth.
after International
SpO2 was Liaison Committee
18% higher on Resuscitation
by 1 min, 13% higher (ILCOR)by <5 min, guidelines
and
10%recommended
higher by 10 min initiating
in babiestheinresuscitation
the group ofof newbornscord
prolonged <35clamping.
weeks GAPadilla with room air and
et al. [14]
built SpO2 and HR curves in healthy-term newborns with delayed cord clamping for aof a
very preterm infants <32 weeks of gestation with FiO 2 0.3, thus discouraging the use
higher
median concentration
of 111 sec. Compared(FiO2with
0.65–1.0)
Dawson’s[39]. curves,
In a recent
theysurvey,
found most NICUs higher
significantly in high-income
SpO2
countries initiated respiratory support in moderate-late
and HR already in the first minute after birth. Thus, the median and IQR of SpO preterm with FiO 2 0.21
2 (%)(43%)
at 1, or
0.3 (36%) [40]. However, only 45% titrated
5, and 10 min after birth were 77 (68–85), 94 (90–96), and FiO 2 to targeted SpO .
96 (93–98), respectively.
2 Interestingly,
HR (beats of the
per 695 respondents,
minute) median whileand IQR 90%athad1, 5,pulseoximeters
and 10 min after in the
birthDR,wereonly14869%(84–170),
had access155to(143–
oxygen
blenders, rendering oxygen titration impossible [40].
167), and 151 (142–161). Badurdeen et al. [16] stabilized preterm infants using physiolog-
ically based cord clamping (PBCC). PBCC is defined as clamping the cord after establish-
ing lung aeration. Preterm infants at ≥32 + 0 weeks GA were randomized to either early
Children 2023, 10, 351 6 of 21

Table 1. Clinical studies comparing higher or lower initial FiO2 for the stabilization of preterm infants
in the delivery room.

Reference Study Design [Initial FiO2 ] Objectives Outcomes

RCT No significant differences
Harling 2005 GA < 31 weeks in lung inflammation.
0.5 vs. 1.0 ↓ lung inflammation
[41] No PO; No SpO2 targets, It is possible to use
n = 52 lower FiO2 .
Cohort ↓ PaO2 at NICU admission
Viability PaO2 at NICU
Stola 2005 [42] WB < 1500 g Variable vs. 1.0 with lower FiO2
admission
PO & target SpO2 ; n = 100 Is possible to use less FiO2 .
RCT Viability; SpO2 targets:
Wang 2008 Supplemental O2
GA < 32 weeks 0.21 vs. 1.0 80–85% at 5 min
[43] necessary in 21% group.
PO & target SpO2 ; n = 41 85–90% at 7 min
Escrig 2008 RCT
SpO2 target 85% at 10 min It is possible use less FiO2 .
[44] GA < 28 weeks
0.3 vs. 0.9 Oxidative stress; Less oxidative stress and
Vento 2009 PO & target SpO2
Inflammation inflammation in 30% arm.
[38] n = 78
Cohort Supplemental O2 is
Viability
Dawson 2009 [45] GA < 30 weeks 0.21 vs. 1.0 necessary in 21% arm.
SpO2 target 90% at 10 min
PO & target SpO2 ; n = 43 Is possible to use less FiO2
PO & target SpO2 ↑ oxidative stress in
Ezaki 2009 [46] Variable vs. 1.0 Oxidative stress
n = 44 100% group.
Titrating is more effective
than static
RCT
Static 1 vs Viability No differences in timing
Rabi 2011 [47] GA < 32 weeks
0.21 titrate or 1.0 titrate SpO2 target 85–92% between the 3 groups to
PO & target SpO2 ; n = 106
reach the target
SpO2 range
RCT
Armanian 2012 GA 29–34 weeks It is possible to use
0.3 vs. 1.0 SpO2 target 85%
[48] PO & target SpO2 less FiO2 .
n = 32
30% is as safe as 65%.
Major neonatal illness
RCT No differences in oxidate
Oxidative stress
GA < 32 weeks stress or BPD.
Rook 2014 [49] 0.3 vs. 0.65 BPD 36 PMA
PO & target SpO2 No differences in
SpO2 target 88–94% at
n = 193 oxidative stress
10 min
biomarkers
It is possible to use
RCT less FiO2
Oxidative stress
GA 24–34 weeks Using 21% resulted in less
Kapadia 2013 [37] 0.21 vs. 1.0 Short-term morbidities
PO & target SpO2 oxidative stress, neonatal
SpO2 target 88–94%
n = 193 morbidities, and need for
oxygen supplementation.
It is possible to use less
RCT Death at 28 days and
FiO2
GA < 30 weeks morbidities
Aguar 2013 [50] 0.30 vs. 0.60 No differences in
PO & target SpO2 SpO2 target 88–94% at
oxidative stress, neonatal
n = 60 10 min
morbidities, or mortality.
Major disability and
RCT
death at 2 y Increased risk of death in
GA < 32 weeks
Oei 2017 [51] 0.21 vs. 1.0 SpO2 target 65–95% at infants <28 weeks in the
PO & target SpO2
5 min and 85–95% until lower FiO2 group.
n = 287
NICU admission
Abbreviations: RCT: Randomized controlled trial; PO: Pulse oximetry; GA: Gestational age; BPD: Bronchopul-
monary dysplasia; PMA: Postmenstrual age; SpO2 : Oxygen saturation; FiO2 : Inspired fraction of oxygen; WB:
Weight birth; NICU: Neonatal intensive care unit; PaO2 : Arterial partial pressure of oxygen. ↑ is increase and
↓ is decrease.

Oei et al. [51], in a randomized controlled non-blinded trial, the TORPIDO trial, com-
pared mortality and clinical outcomes of preterm infants <32 weeks GA initially stabilized
with room air or 100% oxygen. Unexpectedly, in a post-hoc analysis, the room-air group
showed a significantly increased relative risk of death (RR 3.9; CI 1.1–13.4) in the sub-
Children 2023, 10, 351 7 of 21

group of newborns <28 weeks GA. The investigators acknowledged that the trial had been
interrupted before achieving the number of patients calculated to achieve the statistical
power. Moreover, the study had not been powered for this specific secondary outcome.
Notwithstanding, they cautioned against the use of room air in newborns <28 weeks [51].
Lui K et al. [52], employing the Cochrane methodology, aimed to determine whether
using a lower (FiO2 < 0.4) or higher (FiO2 ≥ 0.4) initial oxygen concentration titrated to
targeted SpO2 improved short- and long-term mortality and/or morbidity. The study
included randomized controlled trials but also cluster- and quasi-randomized trials. A
total of 10 trials with 914 infants were included. The results did not show any differences
in mortality compared to discharge or secondary outcomes such as bronchopulmonary
dysplasia (BPD), retinopathy of prematurity (ROP), IPVH, periventricular leukomalacia
(PVL), necrotizing enterocolitis (NEC), or persistent ductus arteriosus (PDA). Moreover,
no differences in neurodevelopmental disability were assessed at 2 years. However, the
quality of the evidence was defined as low due to the high risk of bias and imprecision. The
authors concluded that there is uncertainty as to whether using higher or lower initial FiO2
in preterm <32 weeks GA targeted to SpO2 in the first 10 min after birth has a significant
effect on mortality or major morbidities or long-term neurodevelopmental disability at
2 years of age [52].
In 2019, Welsford et al. [53] carried out a systematic review and meta-analysis com-
paring the clinical outcomes of 5697 preterm infants <35 weeks GA stabilized with an
initial lower oxygen concentration (≤50%) vs. a higher oxygen concentration (>50%). No
differences were found in short-term mortality, neurodevelopment at two years, or other
morbidities such as IVH, BPD, ROP, or NEC among others [53]. It was concluded that there
is no benefit or risk in initiating resuscitation with lower or higher FiO2 [53].

3.3. Long-Term Outcomes and the Initial FiO2

Only a few follow-up studies dealing with the long-term influence of the initial
FiO2 provided during postnatal stabilization in preterm infants have been published (see
Table 2). Soraisham et al. [54], in a retrospective cohort study, assessed death and/or
neurodevelopmental impairment (NDI) in 1509 preterm infants <29 weeks GA stabilized
with FiO2 of 0.21, 1.0, or intermediate values in the delivery room. The composite score
of death or NDI was not different for either of the three groups. However, in survivors,
the adjusted odds for severe NDI were significantly higher in the group resuscitated
with 100% oxygen compared with 0.21 (adjusted OR 1.57, 95% CI 1.05, 2.35). It was
concluded that the use of 100% oxygen could be a triggering factor for brain inflammation
and damage that impaired neurodevelopment in survivors in infancy [54]. In 2011, the
Neonatal Resuscitation Program (USA) recommended the switch from an initial FiO2 of
1.0 to 0.21 for the stabilization of preterm infants. Kapadia et al. [55], in a retrospective
observational study, analyzed the consequences regarding mortality, relevant neonatal
morbidities, and NDI in preterm infants of this significant change. The results showed that
mortality in the newborn period was not different between groups; however, survivors
of the room-air group scored better in the motor composite score of the Bayley III Scale.
Moreover, babies in the low-oxygen period spent fewer days on oxygen and had a lower
incidence of BPD [55]. Boronat N et al. (23) compared mortality and neurodevelopmental
outcomes of extremely preterm infants at the 24-month corrected age assigned to an initial
FiO2 0.3 vs. 0.6–0.65 in two randomized controlled and blinded trials. No differences in
mortality were established. Moreover, Bayley III scales motor, cognitive and language
composites, neurosensorial handicaps, cerebral palsy, or language skills did not show any
differences between groups.
Children 2023, 10, 351 8 of 21

Table 2. Follow-up of clinical studies of preterm infants stabilized with higher vs. lower initial FiO2
in the delivery room.

Neurodevelopmental
Study Design [Initial FiO2 ] Objectives Outcomes
Evaluation Test
RCT
Outcome at
GA ≤ 32 weeks
24 months
Boronat [56] Pulseoximetry 0.3–0.6 Bayley III No differences
postmenstrual
Target SPO2
age (PMA)
n = 206
Retrospective Severe NDI in
cohort Outcome at survivors was
Soraisham [54] 0.21–1.0 Bayley III
GA ≤ 28 weeks 18–21 months PMA significantly higher in
n = 1509 the 100% oxygen group
Retrospective
cohort Outcome at
Kapadia [55] 0.21–1.0 Bayley III No differences
GA ≤ 28 weeks 22–26 months PMA
n = 199
No differences
RCT
Death or NDI at SpO2 < 80% were more
Thamrin [57] GA < 32 weeks 0.21–1.0 Bayley III
24 months PMA likely to die or to
n = 215
have NDI
Abbreviations: RCT: Randomized controlled trial; SPO2 : Oxygen saturation; GA: Gestational age; PMA: Postmen-
strual age; NDI: Neurodevelopmental impairment.

3.4. SpO2 Targets and Oxygen Titration

The initial FiO2 should be titrated to achieve targeted SpO2 s at specific time points
using an air–oxygen blender (Figure 3). The most widely employed references in the
literature are the recommendations of the 2010 American Heart Association resuscitation
algorithm aiming at SpO2 70–75% at 3 min and 80–85% at 5 min [34] and of the European
Resuscitation Council’s (ERC) newborn life support algorithm that recommends reaching
70% at 3 min and 85% at 5 min [36]. These targeted values are close to the median values
of newborn infants not needing resuscitation. However, evidence-based information
regarding the pulse oximetry response to increasing or decreasing FiO2 in preterm infants
is lacking. A group of experts recommended based on their experience that if SpO2 was
below the 10th percentile, then FiO2 should be increased in 10% increments every 30 s
aiming to reach the 25–50th percentile avoiding SpO2 higher than 90% because this may be
associated with PaO2 clearly reaching a toxic value [58].
The target SpO2 range recommended for term and preterm infants are similar, and
most guidelines [7,59] recommend keeping SpO2 above percentile 25 of the reference charts
during the first 10 min after birth. For premature newborns, this recommendation poses
uncertainty since the percentile SpO2 curves were obtained predominantly from healthy-
term infants. Preterm infants included were primarily late preterm, and there was a very
low representation of preterm infants < 32 weeks [13].
In 2006, Canada changed the resuscitation policy from 100% oxygen for all born babies
to 21%. In 2015, Rabi et al. [60], in a retrospective cohort study, compared a historical cohort
of preterm babies ≤27 weeks GA before the change in the resuscitation policy (2004–2006)
with a cohort after the policy change (2007–2009). They found increased mortality and a
higher risk of severe neurological injury in newborns resuscitated initially with room air.
During the study period of 2004–2009, the use of pulse oximetry in the DR was not yet
standardized, nor were there established target SpO2 ranges. Thereafter, reference ranges
for SpO2 and titration policies were implemented. In fact, a meta-analysis in newborns
≤ 28 weeks [61] found no differences in mortality and morbidity when comparing resus-
citation with an initial higher vs. lower oxygen concentration. Intriguingly, they found
differences in mortality depending on whether the studies were blinded (favoring low
FiO2 ) or unblinded (favoring high FiO2 ). Although the cause of this effect is not known,
the authors suggested that the adjustment of FiO2 in response to changes in SpO2 could
be the key to this difference. Hence, in a recent meta-analysis performed in newborns
 Children 2023, 10, x FOR PEER REVIEW 9 of 24

Retrospective
cohort Outcome at 22–26
Kapadia [55] 0.21–1.0 Bayley III No differences
GA ≤ 28 weeks months PMA
Children 2023, 10, 351 n = 199 9 of 21
No differences
RCT
Death or NDI at 24 SpO2 < 80% were
Thamrin [57] GA < 32 weeks 0.21–1.0 Bayley III
months PMA more likely to die
n = 215
<32 weeks, evolving SpO2 in the first 10 min after birth was assessedor[62].
to haveOf
NDInote, only
Abbreviations: RCT: Randomized controlled trial; SpO2: Oxygen saturation; GA: Gestational age;
25% of newborns reached the targetage;
PMA: Postmenstrual SpO (≥80–85%) at impairment.
NDI:2 Neurodevelopmental 5 min. Moreover, not reaching 80%
SpO2 at 5 min was associated with a higher rate of severe IVH, and the longer the time
3.4. SpO2 Targets and Oxygen Titration
needed to reach SpO2 >80%, the higher risk of death. Newborns with lower GA and lower
The initial FiO2 should be titrated to achieve targeted SpO2s at specific time points
initial FiO2 were more likely
using to fail to
an air–oxygen achieve
blender a 3).
(Figure SpO of 80%
The2most widely[62]. In an
employed individual
references patient
in the lit-
meta-analysis from three
eraturerandomized trials comparing
are the recommendations higher Heart
of the 2010 American (>0.6) vs. lower
Association (<0.3) initial
resuscitation
algorithm aiming at SpO2 70–75% at 3 min and 80–85% at 5 min [34] and of the European
FiO2 in preterm infants <32 weeks GA, Oei JL et al. [63] found that initial FiO2 was not
Resuscitation Council’s (ERC) newborn life support algorithm that recommends reach-
associated with differences
ing 70% atin3 death
min andand/or
85% at 5 mindisability
[36]. Theseor cognitive
targeted values scores
are close <85
to theat 2 years of
median
values ofatnewborn
age. However, SpO2 >80% infants not
five minutes needing
was resuscitation.
associated withHowever, evidence-based
decreased infor-
disability/death
mation regarding the pulse oximetry response to increasing or decreasing FiO2 in pre-
and cognitive scoresterm
>85. It may
infants be Aconcluded
is lacking. group of expertsthat, more sobased
recommended thanon the initial FiO
their experience that2 , it is
achieving oxygen saturation
if SpO2 wasabove 80%
below the 10thfive minutes
percentile, after
then FiO birth
2 should be that reduces
increased mortality and
in 10% increments
every 30 sec aiming to reach the 25–50th percentile avoiding SpO2 higher than 90% be-
brain damage in verycause
preterm infants.
this may be associated with PaO2 clearly reaching a toxic value [58].

Figure 3. Oxygen saturation (SpO2 ) according to AHA guidelines should be targeted at 70–75% at
3 min and 80–85 at 5 min. Heart rate (HR) should be targeted at >100 bpm in the first 2–3 min after
birth. Red and blue rectangles define the normality ranges for SPO2 and HR, respectively, at different
postnatal timings after birth (Graph modified from reference [28]). Red and blue rectangles define the
upper and lower of normality ranges for SPO2 and HR, respectively, minute-by-minute in the first
10 min of life.

Oxygen is a potent stimulator of respiratory drive. In experimental studies, it has been

shown that hypoxemia induces respiratory depression [64]. Dekker et al. [65] performed
a small RCT comparing two groups of newborns < 30 weeks who were resuscitated with
30% (n = 24) vs. 100% (n = 20) and observed their effect on spontaneous ventilation. They
retrieved detailed information on the management of oxygen titration during stabilization
and measured oxidative stress biomarkers. They found that the group resuscitated with
100% O2 had a better respiratory effort with significantly higher tidal volumes (VT ), better
oxygenation with a shorter duration of hypoxemia, and a shorter duration of ventilation
compared to the 30% group, with no increased risk of hyperoxia or oxidative stress [65].
However, the rates of intubation in the DR or at <24 h, IVH grades III, death, or BPD were
not different [63]. These results open the door to adequately powered RCTs comparing
the use of higher vs. lower initial oxygen concentrations with rapid titration to avoid an
oxygen overload. Until then, the results of this study should be treated with caution.
Children 2023, 10, 351 10 of 21

3.5. Current Recommendations

Currently, the ILCOR 2020 guidelines [7] recommend the use of lower initial FiO2
(0.21–0.30) for newborns < 35 weeks who receive respiratory support at birth (weak recom-
mendation, with very low certainty of the evidence). However, there are some differences
between the different guidelines. While the American Heart Association (AHA) [30] rec-
ommends an initial FiO2 of up to 0.3, the ERC [59]) recommends using a low oxygen
concentration depending on GA (0.21 in newborns ≥ 32 weeks, 0.21–0.3 in newborns
28–31 weeks, and 0.3 in newborns < 28 weeks).

4. Respiratory Support
Despite the immaturity of the lung, thoracic cage and muscles, and respiratory drive,
approximately 80% of very preterm infants (<32 weeks GA) and even extremely preterm
<26 weeks GA initiate spontaneous breathing or crying at birth. [66,67]. The ILCOR 2020
guidelines recommend nasally administered continuous positive airway pressure (nCPAP)
to provide ventilatory support and establish/maintain lung FRC [7]. The use of tracheal
intubation has declined over the last decade in very preterm infants in the first golden
minutes and may confer advantages toward survival without major morbidity [68].
In recent years, proactive resuscitation has substantially increased the rate of survival
of micro-preemies in the limit of viability (22–24 weeks GA). The ventilatory support
strategies employed to enhance morbidity-free survival rates vary considerably among
institutions reflecting the lack of evidence-based studies, which hampers the establishment
of consensus guidelines as has been acknowledged by different international resuscitation
guidelines [7,30,59,69,70].
We approach different aspects of stabilization and resuscitation during the golden
minutes and focus especially on the subgroup of premature infants born <25 weeks gestation.

4.1. Ventilation in Preterm Infants in the Delivery Room

Immediately after birth, caregivers aim to stabilize preterm infants, independently
of their GA, on non-invasive respiratory support [10]. CPAP remains the most widely
employed mode of noninvasive respiratory support to establish an FRC and achieve
lung recruitment. However, extremely preterm infants frequently require a face mask
for intermittent positive pressure ventilation support (IPPV) with PEEP during the initial
stabilization phase in the transitional period. The effectiveness of face mask PPV requires
choosing the right size to cover the nose and mouth, applying it without excessive pressure
to avoid compression of the trigeminal-cardiac reflex, detecting face mask leakage or airway
obstruction with a respiratory function monitor (RFM), and repositioning the mask [8,71]
(Table 3).

Table 3. Adverse events that reduce the effectiveness of face mask ventilation.

• Error in the size of the facemask.

• Inadequate positioning causing air leak.
• Excessive compression that causes upper airway obstruction.
• Excessive facial compression that causes bradycardia due to the activation of the
trigeminal-cardiac reflex.
• Inadvertent glottis closure impedes air entrance in the lower respiratory airways.
• Volutrauma caused by excessive VT .
• Atelectotrauma caused by insufficient VT
• Barotrauma caused by excessive positive pressure in the airways.
• Ineffective ventilation due to inadequate pressure setting.

Abbreviation: VT : Tidal volume.

4.2. Modalities of Non-Invasive Ventilation: CPAP and PPV Plus PEEP

A general summary of the respiratory approach is depicted in Figure 4. In sponta-
neously breathing preterm infants CPAP with 6 cmH2 O and non-breathing newborns,
Children 2023, 10, 351 11 of 21

intermittent PPV with an inflation pressure of 20 to 25 cmH2 O and PEEP of 5 cmH2 O at a

rate of 40 to 60 breaths/min should be provided early after birth [72]. Ideally, pressures
Children 2023, 10, x FOR PEER REVIEW
should be adjusted according to lung compliance [73] and the patient’s evolving HR 12 and
of 23

SpO2 [9,74,75].

Very preterm Micropreemies

(<32 w GA) 22-23 w GA
DELAYED CORD CLAMPING Consider in
TEMPERATURE CONTROL
At least 30-60 sec 24 w GA
Polyethylene bag
IF RESUSCITATION NEEDED
Radiant heater + mattress DCC during stimulation by an
Servocontrol (after 10 min) obstetrician or midwife

POSITIVE PRESSURE VENTILATION TRACHEAL INTUBATION

MECHANICAL VENTILATION
EARLY SURFACTANT

SPONTANEOUSLY BREATHING NON-SPONTANEOUSLY

NON-INVASIVE VENTILATION BREATHING
nasal or mask CPAP INITIAL NON-INVASIVE
5-6 cmH2O OXYGENATION
VENTILATION
or iFiO2: 0.21-0.3
nasal or mask IPPV + PEEP
nasal or mask IPPV + PEEP 20-25/5-6 cm H2O
20-25/5-6 cmH2O Titrate according
NON RESPONDING
to
TRACHEAL INTUBATION
recommended
AHA 2010 SpO2

Figure4.4.Suggested
Figure Suggestedsteps
stepstotobebefollowed
followedininvery
verypreterm
pretermdelivery.
delivery.TheThemain
mainissues
issuesininthe
thedelivery
delivery
room are (i) maintaining an adequate body temperature and avoiding hypothermia;
room are (i) maintaining an adequate body temperature and avoiding hypothermia; (ii) improving (ii) improving
hemodynamicsstability,
hemodynamics stability,delaying
delayingcord
cordclamping,
clamping,ororincluding
includingan anobstetrician
obstetricianorormidwife
midwifeininthe thefirst
first
seconds of neonatal stimulation; (iii) in spontaneously breathing babies, providing non-invasive
seconds of neonatal stimulation; (iii) in spontaneously breathing babies, providing non-invasive
ventilation with mask or nasal prongs CPAP, trying to avoid intubation. If the respiratory efforts
ventilation with mask or nasal prongs CPAP, trying to avoid intubation. If the respiratory efforts
are insufficient to achieve an adequate FRC, IPPV with PEEP should be provided. (iv) In apneic
are insufficient
babies, to achieve anventilation
initial non-invasive adequate with
FRC,IPPV
IPPVand with PEEP
PEEP should
should bebe provided.
provided. (iv) In
If IPPV andapneic
PEEP
babies,
are notinitial non-invasive
efficient, intubation ventilation with
is required. (v)IPPV and
Initial PEEP
FiO2 of should
0.21 to be
0.3provided.
should beIf titrated
IPPV and PEEP
using an
are not efficient,
air/oxygen blenderintubation
according is required.
to HR and(v)SpO2Initial FiO2 ofModified
response. 0.21 to 0.3 should
from Ventobeettitrated using
al. Pediatr an
Respir
Rev. (2015)blender
air/oxygen [8]. Abbreviations:
according to HR GA:and
Gestational age; w:Modified
SPO2 response. Week; sec:fromSecond;
Vento et DCC: Delayed
al. Pediatr cord
Respir
clamping; min: Minute; CPAP: Continuous positive airway pressure; IPPV:
Rev. (2015) [8]. Abbreviations: GA: Gestational age; w: Week; sec: Second; DCC: Delayed cord Intermittent positive
pressure ventilation;
clamping; min: Minute; PEEP: Positive-end
CPAP: Continuousexpiratory
positivepressure; iFiO2: Initial
airway pressure; IPPV:fraction of inspired
Intermittent oxy-
positive
gen; AHA: American Heart Association; SpO 2: Oxygen saturation.
pressure ventilation; PEEP: Positive-end expiratory pressure; iFiO2 : Initial fraction of inspired oxygen;
AHA: American Heart Association; SpO2 : Oxygen saturation.
For infants requiring higher supplemental oxygen, the CPAP level may be titrated
higherForup to 7–8requiring
infants cm [76]. It has been
higher shown thatoxygen,
supplemental stepwise theincrements
CPAP level of may
PEEPbeafter birth
titrated
higher up to 7–8 cm [76]. It has been shown that stepwise increments of PEEP after birthet
improved the rates of survival and reduced morbidity in preterm infants [77]. Petrillo
al. showed
improved thethat sustained
rates of survivalinflation (SI) followed
and reduced morbidityby nCPAP
in pretermin the range[77].
infants of 6Petrillo
to 8 cmH O,
et 2al.
administered
showed with the RAM
that sustained nasal
inflation (SI)cannula
followed(RAM Nasal Cannula,
by nCPAP in the rangeNeotech
of 6 Products,
to 8 cmH2Va- O,
lencia, CA, USA)
administered with vs.
theface
RAM mask
nasal CPAP
cannulaof 5(RAM
cmH2O, resulted
Nasal Cannula,in a significant reduction
Neotech Products, Va- of
the intubation
lencia, CA, USA) rate
vs.inface
the DR
mask[78].
CPAP Increasing
of 5 cmH the2 O,
pressure
resulted in in
theainitial minutes
significant after birth
reduction of
should
the be carefully
intubation rate in considered.
the DR [78].Hence,
Increasing75%the of neonates
pressure in born
the at <29 minutes
initial weeks’ GA resusci-
after birth
tated with
should a T-piece
be carefully resuscitator
considered. (TPR),
Hence, 75%setof with a peak
neonates born inspiratory
at <29 weeks’ pressure (PIP) of 24
GA resuscitated
and aPEEP
with of 6resuscitator
T-piece cmH2O, received VT with
(TPR), set > 6 mL/kg,
a peak which can injure
inspiratory pressure the (PIP)
lungsofand contribute
24 and PEEP
ofto6IVH
cmH[79].
2 O, received VT > 6 mL/kg, which can injure the lungs and contribute to IVH [79].
No
Nooptimal
optimal CPAP pressure has hasbeenbeenestablished.
established.However,
However, preclinical
preclinical studies
studies in
in pre-
preterm
term lambslambs [80,81]
[80,81] andandrabbits
rabbits[82]
[82]compared
comparedtitrated
titrated pressures
pressures in aa range
rangeof of0–12
0–12cmH
cmH22O O
and concluded that CPAP levels >10 cmH O improved oxygenation
and concluded that CPAP levels >10 cmH2 2O improved oxygenation [71], suggesting that [71], suggesting that
uniform
uniformlung lungaeration
aerationisisbest
bestachieved
achievedby bystarting
startingrespiratory
respiratorysupport
supportwithwithhigher
higherPEEP
PEEP
levels.
levels. However,
However, higher higher PEEP
PEEP levels
levels should
should be becautiously
cautiouslyapplied
appliedbecause
becausetheytheycould
could
overexpand
overexpandthe the lungs
lungs and decrease pulmonary
and decrease pulmonaryblood bloodflow
flowand andthe thebreathing
breathing rate
rate [71].
[71]. In
an RCT, the use of CPAP  8 cmH2O during resuscitation significantly increased the rate
In an RCT, the use of CPAP ≥ 8 cmH 2 O during resuscitation significantly increased the
rate of pneumothoraces
of pneumothoraces [83],[83],
whilewhile
infants infants on CPAP
on CPAP levelslevels
of 5 toof7 cmH
5 to 72OcmH O did
did 2not not this
exhibit ex-
[84]. In addition, inadvertent PEEP above the set value should be taken into consideration
[73,76].
Children 2023, 10, 351 12 of 21

hibit this [84]. In addition, inadvertent PEEP above the set value should be taken into
consideration [73,76].

4.3. Type of Devices: T-Piece Resuscitator (TPR), Self-Inflating Bag (SIB), Mechanical Ventilators
It is mandatory that the ventilation devices employed in the DR provide PIP, PEEP,
and/or CPAP [8]. The self-inflating bag (SIB) and the T-piece resuscitator (TPR) are the two
most common manual ventilation devices employed for respiratory support in DR. How-
ever, CPAP is not applicable with SIB. Moreover, the SIB expiratory valves are unreliable
for providing PEEP with very low VT [85]. However, the use of SIB is essential for neonatal
resuscitation in regions where pressurized gases are not readily available [7].
Experimental studies suggest the benefit of using devices providing controlled levels
of PEEP and PIP to assist in the establishment of pulmonary FRC during the transition and
reduce lung damage secondary to barotrauma [86,87]. In manikin studies, TPR delivered
more consistent PPV and more homogeneous VT than SIB [88–90]. In preterm neonates,
TPR resulted in better control of PaCO2 levels compared to SIB during surfactant admin-
istration [74]. In addition, Roehr et al. [91], in a recent systematic review, identified new
evidence that pointed towards improved survival, decreased BPD, and fewer intubations
at birth in preterm infants stabilized with TPR [92,93].
It is currently unclear which TPR is most effective for applying CPAP at birth. The
effect of pressure stability and expiratory resistance was compared with seven CPAP
systems in simulated breath profiles. Neopuff (Fisher & Paykel Healthcare, Auckland,
New Zealand) and Medijet (Medin CNO Medical Innovations, Puchheim, Germany) had
the highest pressure instability and imposed work of breathing. Benveniste (gas-jet valve
Dameca, Copenhagen, Denmark, and Prongs Firma H. Mortensen, Randers, Denmark),
Hamilton Universal Arabella (Hamilton Medical AG, Bonaduz, Switzerland), and Bubble
CPAP (Fisher and Paykel Healthcare, Auckland, New Zealand) showed intermediate
results. AirLife (Cardinal Health, Waukegan, IL, USA) and Infant Flow (Viasys Healthcare
Respiratory Care, Palm Springs, CA, USA) showed the lowest pressure instability and
imposed work of breathing and the lowest decrease in delivered pressure when challenged
with a constant leak [94]. A new TPR device (rPAP) that uses a dual-flow ratio valve
(fluidic flip) to produce PEEP/CPAP, designed to be used with nasal prongs, showed low
imposed work of breathing and kept PEEP at the set value due to inherent TPR device
design characteristics, decreasing the rate of intubation or death in the DR [73,95].
Ventilators are commonly used for CPAP delivery and PPV during transport and
in the NICU rather than in the DR [9]. However, in the Uppsala University Children’s
Hospital (Sweden) and Kitasato University, Kanagawa (Japan), babies in the limit of
viability (22–23 weeks GA) are intubated immediately after birth and placed on ventilators
with targeted VT avoiding bag and mask ventilation or CPAP [70].

4.4. Interfaces for Delivering Mask Non-Invasive Ventilation

Two different types of masks are available for mask PIP or CPAP, anatomic or round
masks. O’Donnell et al. found no differences in air leaks between the two different mask
types [96]. The effectiveness of the face mask PPV depends on achieving an adequate seal
to avoid airway obstruction and mask leak, gently placed to avoid the potential activation
of the naso-trigeminal reflex [75,97]. Short binasal prong interfaces typically had greater
resistance at the smallest assessed sizes, which could deliver insignificant VT [98]. The
experience with its application is limited, but RAM nasal cannula reported a decrease in
DR intubation [99]. Small nasal masks can be used as an alternative to binasal prongs
generating less intrinsic resistance compared with short binasal prongs [98]. The use of
a single nasal tube causes large leaks, more obstruction, delays PPV initiation because of
placement, and lower VT and higher requirements for supplemental oxygen compared
with the face mask [100]. Effective ventilation decreasing early neonatal mortality and brain
injury could be more easily achieved with a supraglottic airway device than with a face
mask [101,102]. However, this device has been underutilized due to inappropriate sizes for
Children 2023, 10, 351 13 of 21

premature babies, providers’ limited experience, limited knowledge of its functionality, and
likely due to a lack of evidence. A high-flow nasal cannula (6–8 L/min) or non-invasive
high-frequency oscillation in the DR is not yet recommended until reliable evidence is
available [9].
The trigeminal-cardiac reflex and laryngeal closure may reduce the effectiveness
of non-invasive respiratory support in premature infants immediately after birth [103].
Experimental studies in rabbits have shown that postnatal hypoxia may lead to the closure
of the glottis, rendering PPV ineffective [103]. Moreover, inadequate patency of the glottis
reduces the effectiveness of SI [71]. The facial compression caused by the application of
a face mask may cause intense bradycardia by inducing a trigeminal-cardiac reflex [104].
Kuypers et al. showed that apnea and/or bradycardia occurred after applying either
bi-nasal prongs or a face mask on the face for respiratory support in preterm infants at
birth [105]. Cutaneous stimulation and supporting spontaneous breathing could enhance
the success of non-invasive ventilation by ensuring that the larynx remains open [106].

4.5. Heated and Humidified Gas (HHG)

Heating and humidification of inspired gases for the initial stabilization of preterm
infants and during transport to the neonatal unit improve the admission temperature in
preterm infants, especially below 28 weeks GA [107,108]. Notwithstanding, recommenda-
tions for conditioning gases during newborn stabilization cannot yet be given based on the
limited evidence currently available, as has been underscored in the last ILCOR CoSTR
survey [7].

4.6. Endotracheal Intubation

ILCOR 2020 guidelines [7] recommended the use of CPAP rather than intubation for
spontaneously breathing preterm infants with respiratory distress requiring respiratory sup-
port in the delivery room. Both RCTs and meta-analyses with high-quality evidence have
shown a reduction in the combined outcome of death and BPD when starting treatment
with CPAP compared with intubation and ventilation in very preterm infants with respira-
tory distress [83,84,109–113]. The meta-analysis reported no differences in the individual
outcomes of mortality, BPD, pneumothorax, IVH, NEC, or ROP [112].
ERC 2021 guidelines suggested considering intubation in the case of needing surfactant
administration in the DR [59]. However, in a recent Cochrane review, surfactant delivery
via a thin catheter to spontaneously breathing preterm infants compared with surfactant
administration through an endotracheal tube (ETT) was associated with a decrease in the
risk of death, BPD, and severe IVH [114].

4.7. Resuscitation of Extreme Preterm in the Limit of Viability

Extremely preterm infants (<28 weeks GA) require early prophylactic non-invasive
respiratory ventilation (NIV) initiated in the DR [59,66,69]. However, the most extremely
preterm infants, also known as micro-preemies (22–24 weeks GA), require immediate
intubation and mechanical ventilation at birth followed by prolonged dependency on
non-invasive respiratory support and supplemental oxygen therapy [66]. The SUPPORT
trial showed more favorable outcomes in infants who received early nCPAP treatment in
comparison with surfactant treatment in the DR [84]. However, infants <24 weeks GA were
not included in this study because pre-study trials had shown nCPAP failure in 23-week
infants, similar to what was reported in previous studies, such as the COIN trial [83].
Consequently, the number of micro-preemies enrolled in clinical trials has been too small
to show clear scientific evidence of the relationship between intubation and an increased
risk of BPD.
Available evidence of the effectiveness of NIV applied to this category of patients is
limited, and optimal CPAP pressure to obtain a stable FRC is not known. Of note, it is very
unusual for micro-preemies to breathe spontaneously. Consequently, tracheal intubation
and mechanical ventilation in infants born at 22–23 weeks GA immediately after birth has
Children 2023, 10, 351 14 of 21

become a standard of care in centers with a proactive attitude towards the treatment of
these patients in the limits of viability [95,115,116].
There are minimal data on micro-preemies in relation to the necessary ventilation
pressures. On the one hand, some studies show that a peak inflation pressure of 20 cmH2 O
might be too low to effectively recruit the lungs in extremely premature infants [117–119].
In contrast, Bhat et al. performed a prospective study in preterm infants <34 weeks GA
to assess combinations of inflation pressures and times and the resulting expiratory VT
levels using an RFM. Inflation pressure was the key factor producing significantly higher
expiratory VT , and a longer inflation time was not necessary to increase expiratory VT [118].
Murthy et al. found that only 27% of infants had expiratory VT greater than 4.4 mL/kg,
but these VT were measured only for the first five inflations via ETT when adequate VT
rarely occurs [117]. On the other hand, RCT in the DR with a fixed initial PIP and settings
according to VT [75] show different pressure levels to achieve adequate lung recruitment
depending on GA, with PIP less than 20 cmH2 O. This strategy is also used regularly in
Japanese groups with an active attitude toward micropremies [115]. We suggest a set of
maneuvers and strategies for the management of premature infants at the limit of viability
(22–23 weeks GA) described in Table 4.

Table 4. Strategies for the management of preterm infants in the limit of viability (22–23 weeks
GA) in the golden hour following the suggestions of neonatal centers with greater experience in
the treatment of micro-preemies [13,66,70,75,115,116]. Modified from Norman et al. Semin Fetal
Neonatal Med. 2022 [27].

Assemble designated staff. Brief with attending team.

Before birth Prepare delivery room. Use checklists.
Information to parents.
Plastic bag without drying.
Thermal care Radiant warmer, room temperature 21–25 ◦ C.
Humidified, tempered (36–37 ◦ C) gases for ventilation.
Delayed cord clamping [12] Any gestational age if resuscitation isn’t needed.

- 22 weeks’ GA: intubation.

Initial ventilatory support at stabilization (while placing - 23 weeks’ GA: intubation most likely needed.
ECG leads on the infant’s chest) - 24 weeks’ GA: nCPAP, PPV by TPR or ventilator on mask/nasal
prongs, DR intubation if needed

- 22–23 weeks: 2.5 mm (two attempts) or 2.0 mm/5.5 cm at lip.

ETT size internal diameter/intubation depth
- 24 weeks: 2.5 mm/5.5–6 cm at lip.

- 22 weeks’ GA: 18 cmH2 O

Initial PIP set not to exceed 20 cmH2 O
- 23 weeks’ GA: 19 cmH2 O
(TPR flow 10 L/min) [70,75]
- 24 weeks’ GA: 20 cmH2 O

set volume targeted 2.5 mL (5 mL/kg),

If use RFM
Ti set <1 s and RR 60/min guide by CO2 et
0.3
Initial FiO2 [13]
Titration to achieve SpO2 targets of 80–85% at 5 min
CV: PIP = 20–22 cmH2 O, PEEP = 5 cmH2 O, backup
frequency = 40–60/min, VT = 4–6 mL/kg.
Suggested first intended ventilatory settings [70,75,115] HFOV + VThf 1 mL: MAP = 10–12 cmH2 O, frequency = 14–15 Hz,
initial amplitude 40–50 cmH2 O *, I:E 1:2 (1:1 if >15 Hz).
Saturation limits: 90–92%.
Surfactant administration within 2 h of life
After birth Debriefing with the attending team
CV = conventional ventilation, ETT = endotracheal tube, FiO2 = Fraction of inspired oxygen, GA = gestational
age, HFOV = High Frequency Oscillatory Ventilation, TPR= T-piece resuscitation, MAP = mean airway pressure,
nCPAP = Continuous positive airway pressure administered nasally, PEEP = positive end-expiratory pressure,
PIP= peak inspiratory pressure, PPV = Positive pressure ventilation, RR = Respiratory rate, Ti = inspiratory time,
VT = tidal volume, VThf = volume guarantee in high frequency oscillator ventilation. I:E = inspiration expiration
ratio. * After recruitment, delimit 15–20 cmH2 O above what is necessary to reach set VThf .
Children 2023, 10, 351 15 of 21

4.8. Respiratory Function Monitor (RFM)

The effectiveness of mask ventilation can be improved using an RFM. There are
different models and brands of RFM but all of them provide continuous real-time infor-
mation of inspiratory and expiratory graphs, the respiratory rate, VT , SpO2 , or air leaks.
This information allows one to detect problems/pitfalls associated with mask ventilation
early [75,97,120]. RCTs comparing the use of an RFM in addition to clinical assessment vs.
clinical assessment alone during mask ventilation in the DR of infants born <37 weeks’
gestation showed that using an RFM to guide VT delivery might reduce injury and improve
outcomes [75,120,121]. In a meta-analysis of three RCTs enrolling 443 infants, the pooled
analysis showed no differences in the rates of death before discharge with an RFM vs. no
RFM. However, a significant reduction for any brain injury considered a combination of
IVH and PVL (RR 0.65 (0.48 to 0.89), p = 0.006) and IVH (RR 0.69 (0.50 to 0.96), p = 0.03)
was assessed in infants receiving PPV with an RFM vs. no RFM. Moreover, these studies
reported that fewer infants in the RFM-visible group had expired VT > 8 mL/kg, compared
with the no-RFM group [122]. However, there is insufficient evidence to make a recom-
mendation for or against its use [7,123]. Long-term neurological outcomes to assess the
efficacy of RFMs during mask ventilation in preterm infants will help to make a strong
recommendation for its use in the delivery room. Perhaps its cost-effectiveness and the
training requirements precluded the generalized use of RFM [124]. The monitoring of
non-invasive ventilation effectiveness (either by capnography or RFM) is becoming more
common outside research settings to detect adverse events to be able to reposition the mask
and thus decrease them [122,125,126].

5. Conclusions
At present, the optimal initial FiO2 and how to titrate oxygen during the stabilization
of very preterm infants in the delivery room are yet unknown.
Optimizing ventilation to establish a good lung capacity and cutaneous stimulation to
trigger spontaneous breathing both contribute to the establishment of effective respiration
in the initial minutes after birth.
Despite the initial FiO2 , titrating oxygen to achieve SpO2 targets of 80–85% five minutes
after birth seems appropriate to reduce the damage caused by hypoxia or hyperoxia during
resuscitation in the DR.
Reference ranges in newborns with deferred, as compared to immediate, cord clamp-
ing show differences in SpO2 and HR in the initial minutes after birth.
The initiation of ventilation with an intact cord (physiologic-based cord clamping)
seems to be a promising strategy to enhance oxygenation and achieve hemodynamic
stabilization in the initial minutes after birth; however, until more evidence is available,
caution is advised.
The application of optimal strategies to use NIV modalities immediately after birth
is important to establish an FRC to reduce the need for intubation, invasive mechanical
ventilation, mortality, and BPD.
Implementing a resuscitation bundle involves determining the appropriate size and
sealed mask, head repositioning, the opening of the mouth, increasing the pressure when
indicated and regulating it depending on the patient’s response and changes in lung
compliance, and debriefing after each intubation.
TPR allows accurate PPV with PEEP. There is no current evidence to suggest one
interface is better than another. Evidence was insufficient to recommend the use of heated,
humidified gases for assisted ventilation.
Feedback devices such as RFM can help detect adverse events.
To reduce unwarranted variability in the care of most extremely preterm infants
between 22 and 23 weeks of GA, we propose respiratory support including immediate oral
intubation, applying TPR immediately, and avoiding bag ventilation either by mask or
ETT, ECG leads, or an ETT secured lip level. This approach could be considered for use in
preterm infants of 24 weeks GA.
Children 2023, 10, 351 16 of 21

Author Contributions: Conceptualization, R.E.-F. and M.V.; methodology, R.E.-F.; writing—original

draft preparation, R.E.-F., G.Z.-S., A.A.-A., M.G.-M., J.D.T.-P. and M.V.; writing—review and editing,
R.E.-F., G.Z.-S. and M.V.; supervision, M.V. All authors have read and agreed to the published version
of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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