Pediatrics and Neonatology 63 (2022) 341e347
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: http://www.pediatr-neonatol.com
Review Article
New developments in neonatal respiratory
management
I-Ling Chen a, Hsiu-Lin Chen a,b,*
a
Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, No. 100,
Shih-Chuan 1st Road, San Ming District, Kaohsiung, Taiwan
b
Department of Pediatrics, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, San Ming
District, Kaohsiung, Taiwan
Received Sep 26, 2021; received in revised form Jan 28, 2022; accepted Feb 14, 2022
Available online 16 March 2022
Key words
less invasive
surfactant
administration
(LISA);
neonates;
neurally Adjusted
Ventilatory Assist
(NAVA);
noninvasive
Ventilation (NIV);
volume guarantee
ventilation
Abstract Respiratory distress syndrome (RDS) is the major cause of respiratory failure in preterm infants due to immature lung development and surfactant deficiency. Although the concepts and methods of managing respiratory problems in neonates have changed continuously,
determining appropriate respiratory treatment with minimal ventilation-induced lung injury
and complications is crucially important. This review summarizes neonatal respiratory therapy’s advances and available strategies (i.e., exogenous surfactant therapy, noninvasive ventilation, and different ventilation modes), focusing on RDS management.
Copyright ª 2022, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).
1. Introduction
With the development of neonatal medicine and intensive
care, the concepts and methods of managing respiratory
problems in neonates have been changing continuously.
Respiratory distress syndrome (RDS) is a major cause of
respiratory failure in preterm infants due to immature lung
development and surfactant deficiency. Important aspects
such as exogenous surfactant therapy, use of noninvasive
ventilation and different ventilation modes to avoid intubation, ventilation-induced lung injury, and comorbidities
have led to an increased interest in RDS. This review summarizes the advances and available strategies for neonatal
respiratory therapy, focusing on the management of RDS.
* Corresponding author. Department of Pediatrics, Kaohsiung Medical University Hospital No. 100, Tzyou 1st Road, Kaohsiung, Taiwan.
E-mail address: ch840062@kmu.edu.tw (H.-L. Chen).
https://doi.org/10.1016/j.pedneo.2022.02.002
1875-9572/Copyright ª 2022, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
I.-L. Chen and H.-L. Chen
2. Administration of exogenous surfactants
major morbidities among infants who survive extremely
preterm birth. Noninvasive ventilation (NIV) is a common
treatment for preterm infants with RDS. NIV helps avoid
intubation or provides post-extubation respiratory support,
thereby minimizing ventilator-induced lung injury and
improving the outcomes.
Nasal CPAP (NCPAP), nasal intermittent positive pressure
ventilation (NIPPV), bi-level positive airway pressure
(BiPAP), and high-flow nasal cannula (HFNC) are common
types of NIV. NCPAP delivers a constant positive pressure
throughout the respiratory cycle to recruit the collapsed
alveoli and reduce the airway resistance, thereby attaining
functional residual capacity (FRC) and preventing airway
collapse. NIPPV delivers intermittent positive pressure
driven by flow at set intervals based on NCPAP. BiPAP provides cycles with high and low positive pressures at set intervals. HFNC delivers heated and humidified oxygen at a
flow rate of 2e8 L/min through a nasal prong and generates
a positive end-expiratory pressure. HFNC can reduce the
physiological dead space, decrease nasopharyngeal airway
resistance, and prevent airway mucosa dryness and injury.
There is no standardized protocol for determining the
optimal NIV treatment in terms of effectiveness and timeliness. Here, we discuss some current comparisons of NIV
use. In very low birth weight preterm infants with RDS,
NIPPV and NCPAP showed comparable results in terms of
extubation failure, death or BPD, intraventricular hemorrhage, air leaks, necrotizing enterocolitis, and duration of
respiratory support.10 However, synchronized NIPPV
(SNIPPV) and SNIPPV þ NCPAP exhibited a higher rate of
successful extubation and removal of NIV within 1 week
when compared with NCPAP.11 Moreover, SNIPPV significantly reduced the incidences of desaturation, bradycardia, and apnea in preterm infants.12 These findings
suggest that synchronization plays a crucial role in
providing efficient respiratory support. Asynchronies may
alter spontaneous breathing rhythm, elevate the work of
breathing (WOB), and lead to abdominal distension.
Indeed, some studies have demonstrated the efficiency of
SNIPPV in reducing the WOB,13 improving gas exchange,14
and improving chest wall stability by increasing the flow
delivery in the upper airway15 of preterm infants. Failure of
SNIPPV was associated with the grade of RDS, antenatal
steroid use, and mean airway pressure.15 The incidence of
NCPAP failure was higher than that of BiPAP or NIPPV failure
within the first 72 h of life in preterm infants with RDS.16,17
Failure of NCPAP was associated with lower antenatal steroid administration and smaller gestational age.17 Additionally, use of BiPAP shortened the duration of respiratory
support without interfering with the incidence of BPD,
incidence of retinopathy of prematurity, and lung function
at 1 year of age.18 Use of high pressures during CPAP
(9 cmH2O) has been recently suggested in preterm infants
who are likely to require an alternative mode of noninvasive support. Use of high CPAP pressures did not have a
negative impact on the cardiac output or WOB when
compared with NIPPV in preterm infants,19 and there was
no difference in the incidence of failure between these two
methods.20 The incidence of pneumothorax was 9% in
extremely preterm infants treated with CPAP, and the use
of high pressures during CPAP was associated with a higher
rate of pneumothorax, probably due to lung overexpansion
Since surfactant deficiency is a well-established factor
associated with RDS in preterm infants, administration of a
surfactant improves pulmonary gas exchange, reduces the
need for mechanical ventilation, and reduces the risk of
bronchopulmonary dysplasia (BPD).1 The method of exogenous surfactant delivery has evolved from endotracheal
administration of a surfactant bolus during mechanical
ventilation to the INtubate-SURfactant-Extubate (INSURE)
procedure. The INSURE procedure comprises intubation followed by administration of a surfactant, early extubation,
and continuous positive airway pressure (CPAP) support.
Although INSURE might help minimize the complications
associated with mechanical ventilation, its success rate is
not very high. INSURE was successful in approximately 30% of
preterm infants below 32 weeks of gestational age, while
those failed INSURE required longer periods of ventilation or
re-intubation.2 Sedation is required during INSURE and
placement of an endotracheal tube may cause pain, stress,
or hemodynamic complications. A systemic review reported
that failure of INSURE was related to extremely low birth
weight, samll gestational age, and severe RDS.3
Less invasive surfactant administration (LISA), also known
as minimally invasive surfactant administration, aims to
introduce an adequate amount of surfactant into the trachea
via a small-diameter catheter placed orally or nasally beyond
the vocal cord. LISA allows infants to breathe spontaneously
during the delivery of the surfactant. Early respiratory support
using CPAP and rescue surfactant administration using LISA are
recommended for spontaneous breathing of preterm infants
at a risk of RDS. A previous meta-analysis reported that infants
treated with LISA exhibited lower rates of BPD, decreased
need and duration of respiratory support, and lower rates of
CPAP failure when compared with other methods of surfactant
delivery.4,5 LISA was also associated with reduced duration of
hospital stay, reduced duration of oxygen supplementation,
lower rates of other common neonatal morbidities, such as
intraventricular hemorrhage, and lower rate of interventions
for retinopathy of prematurity.6 In a study with 2-year followup, LISA exhibited no significant negative effects on body
length, body weight, and neurodevelopment of preterm infants.7 Despite these findings supporting the feasibility and
safety of LISA, some relevant adverse events of LISA have been
reported, including tracheal surfactant reflux, bradycardia,
hypoxia, need for intubation, unilateral deposition of the
surfactant, and mucosal bleeding.8 Failure of LISA may be
associated with lower gestational age and the extent of lung
immaturity.6
Although analgesia or sedation is not mandatory during
LISA, it can still be used in vigorous infants for increased
comfort. Prevention of pain and stress is crucial in clinical
practice. Moreover, it is influential in cognitive and motor
development in infants. Notably, even low-dose sedation
may increase desaturation and offer prolonged respiratory
support.9
3. Noninvasive ventilation
BPD is associated with the duration of invasive mechanical
ventilation and oxygen supplementation. It is one of the
342
Pediatrics and Neonatology 63 (2022) 341e347
in very preterm infants.21 Hence, we cannot ignore the
negative outcomes associated with the use of high pressures during CPAP.22 The incidence of HFNC failure, which is
associated with histologic chorioamnionitis, treated patent
ductus arteriosus, and lower gestational age, was higher
than the incidence of NCPAP or NIPPV failure in preterm
infants.23 Moreover, a meta-analysis demonstrated a higher
failure rate of HFNC compared to that of NCPAP despite the
low incidences of nasal trauma and pneumothorax in
HFNC.24
Diagnostic accuracy is crucial in predicting the failure of
NIV in infants. Assessment of diaphragmatic kinetics by
measuring the peak velocity of the right diaphragmatic
excursions (RD-PV) detects diaphragmatic activity suggestive of fatigue. The ratio of oxygen saturation (SpO2)/
fraction of inspired oxygen (FiO2) (SF ratio) was inversely
related to RD-PV recorded using pulsed-wave tissue
Doppler. Despite the potential fluctuations in SpO2, low SF
ratio and high RD-PV successfully predicted NCPAP failure in
preterm infants with RDS.25 This finding also suggests that
failure of NIV in preterm infants might be associated with
prolonged high diaphragmatic activity, which is caused by
the inability to maintain FRC.
apnea occurs for a predetermined time, pressure-controlled
backup ventilation is provided until spontaneous ventilation
resumes. NAVA was shown to decrease the number of
desaturations and the incidence of bradycardia in preterm
infants with apnea of prematurity when compared with
nasal CPAP.33
Increasing the NAVA value initially increased the PIP
while maintaining a constant EAdi until the breakpoint (BrP)
is reached. Further increases in NAVA decreased the EAdi,
while PIP was stabilized.34 BrP value is unique for every
individual. Below BrP, unloading of the diaphragm is insufficient to increase the NAVA level, PIP, and tidal volume and
maintain a high EAdi. Upon reaching BrP, which reflects
adequate unloading of the diaphragm, PIP remains unchanged and EAdi starts to decrease. This neural feedback
mechanism of NAVA ventilation prevents lungs from overdistention.34 Therefore, extubation criteria based merely
on airway pressures and spontaneous breathing efforts
might not be applicable during NAVA ventilation. Intubated
preterm infants with RDS who were treated with invasive
NAVA exhibited lower PIP than those in conventional
mode.35 However, preterm infants exhibited higher BrP,
PIP, and EAdi after extubating from invasive NAVA to NIV
with NAVA. These findings suggest that clinicians should be
mindful of certain aspects including immature neural
feedback mechanisms in preterm infants, inefficiencies of
NIV ventilation, and requirement of a higher NAVA level
while transitioning from invasive NAVA to NIV with NAVA.36
4. Neurally adjusted ventilatory assist
Neurally adjusted ventilatory assist (NAVA) is a mode of
mechanical ventilation that triggers and cycles inspiratory
assistance in proportion to the electronic activity of the
diaphragm (EAdi), allowing infants to control their own
peak inspiratory pressure and tidal volume on a breath-tobreath basis. The EAdi signal is assessed at the distal
esophageal level using electrodes embedded within a
nasogastric tube. The maximum EAdi correlating with the
intensity of diaphragmatic contraction represents the
inspired tidal volume. Tonic EAdi is associated with the
persistence of diaphragmatic contraction during expiration,
maintaining the end-expiratory lung volume and FRC. A
higher tonic EAdi might be needed to maintain the endexpiratory lung volume and FRC in the presence of alveolar
instability and low compliance. The patterns of neural
breathing in preterm infants are quite variable26 and
continuous adjustment of NAVA according to the inspiratory
time and respiratory rate may help in better adaptation to
the infants’ demands.
EAdi is independent of air leaks during NIV. NIV with NAVA
is feasible and well tolerated in preterm infants with physiological benefits, such as improved patient-ventilator synchronization and reduced peak inspiratory pressure (PIP),
FiO2, frequency, and length of desaturations.27e30 NIV with
NAVA improved diaphragmatic unloading, possibly leading to
a reduction in the WOB. A significant improvement in the
WOB-related indices was also observed in infants with severe
bronchiolitis after transition from NCPAP to NIV with NAVA.31
NAVA was superior to NIPPV in reducing bradycardic events in
infants with very low birth weight.32
In addition to methylxanthine therapy, CPAP is the
standard treatment for apnea of prematurity. However,
CPAP often fails in infants with apnea of prematurity due to
inadequate respiratory support during the apneic period.
NAVA can detect apneas and offer rescue ventilation. If
5. Volume guarantee ventilation
Wide fluctuations in tidal volume in ventilated infants are
among the mechanisms of respiratory instability, which can
lead to frequent fluctuations in SpO2. Volume guarantee
ventilation (VG) is a pressure-controlled ventilation mode.
Breathing in VG is pressure-limited with a decelerating
flow. VG uses a feedback loop for automatic adjustment of
PIP to deliver a set tidal volume based on variations in lung
compliance, airway resistance, and spontaneous respiratory effort of the patients.
The VG mode can be used in combination with assistcontrol (A/C), synchronized intermittent mandatory ventilation (SIMV), or pressure-support ventilation (PSV). The
effects of VG vary when combined with different modes in
preterm infants. The VG periods of A/C and SIMV were
associated with a lower PIP and fewer incidences of
excessively large tidal volumes in preterm infants with
RDS.37 The incidence of hypocapnia was lower in A/C þ VG
than in A/C alone.38 Despite similar morbidity, mortality,
and incidence of pulmonary inflammation between
PSV þ VG and SIMV þ VG, PSV þ VG provided more breaths
with tidal volume closer to the set value without overventilation and hypocarbia in ventilated preterm infants
with RDS.39 Decreased need for re-intubation was also
evident in PSV þ VG for preterm infants with RDS.40 Table 1
summarizes the different modes in combination with VG.
High-frequency tidal volume (VThf), which is inversely
proportional to the oscillation frequency, depends on the
oscillation amplitude and inspiratory time in high-frequency
oscillatory ventilation (HFOV). Chest oscillations and tidal
volume could vary under the same pressure amplitude and
343
I.-L. Chen and H.-L. Chen
Table 1
Summary of the different modes in combination with Volume guarantee ventilation (VG).
Mode
A/C þ VG
SIMV þ VG
PSV þ VG
Trigger
Ventilator-time
Patient-flow/pressure
Volume
All are mechanically
supported to reach desired
volume
Ventilator-time
Patient-flow/pressure
Volume
Only intermittent
mandatory ventilatory
breathes are supported
Patient- flow/pressure
A patient with normal
inspiratory drive, but the
respiratory muscles are still
not very strong.
A patient with normal
inspiratory drive, but the
respiratory muscles are still
not very strong.
There is an attempt to
reduce the number of
ventilators assisted breaths
or a patient is planned to
wean from respiratory
support.
Control
Breath
When to use
Volume
If breath delivers a tidal
volume below desired, it is
transitioned to
mechanically supported
A spontaneously breathing
patient requires a
substantial level of support
and has a vigorous
ventilatory drive.
A/C: assist-control; SIMV: synchronized intermittent mandatory ventilation; PSV: pressure-support ventilation.
infants exhibit slightly higher deposition of the aerosols in
the lung compared to term infants, which might be due to
their lower inhaled flow rates.45
Drug delivery to preterm infants can be performed with
temporary disconnection from NIV (e.g., pressurized
metered-dose inhaler with a spacer chamber and a mask) or
integration within the NIV circuit (e.g., nebulizers). Using
pressurized metered-dose inhalers in preterm infants
resulted in less than 1% aerosol deposition in the lungs.46
Cessation of respiratory support may not be the most
optimal approach for critical patients. Aerosolized medication administered during NIV offers better and quicker
clinical effects without interrupting the delivery of oxygen
and positive pressure. NCPAP could deliver aerosolized
medications effectively; however, the efficacy depended
on the type of device and position of the nebulizer.47
A pilot phase I clinical trial demonstrated the feasibility
of aerosolized surfactant using a low-flow jet nebulizer for
the treatment of RDS in preterm infants in various NIV
settings including NCPAP, NIPPV, and HFNC.48 Aerosolized
surfactant delivery might reduce the need for airway
manipulation and requires less technical skill than LISA.
Nevertheless, it is still challenging to deliver aerosolized
medications during NIV. Therefore, nasal cannulas are
frequently used for the delivery of aerosolized medication
during NIV and for providing oxygenation with high gas flow
rates. Aerosol particles with diameters of approximately
1.5 mm are ideal for high-efficiency nose-to-lung aerosol
delivery in infants through a nasal cannula.49 However,
aerosol deposition in the nasal cavity and aerosol leakage
through the nostrils may limit delivery to the lungs. The
cannula flow rate significantly affects the pulmonary
dosing. Although lower cannula flow rates reduce aerosol
deposition in the nasal cavity, they are below those
required for oxygen support.50,51 Another interface facial
mask, in addition to potential leakage, its large volume may
accumulate aerosol particles. Synchronizing the production
of aerosolized medication with inhalation improves its
frequency in HFOV due to different lung mechanics and
patient-ventilator interactions. In HFOV þ VG, the ventilator
measures the volume in each breath and automatically adjusts the amplitude pressure to deliver a set VThf to improve
CO2 clearance. The mean VThf was higher and was maintained more consistently in HFOV þ VG when compared with
HFOV alone.41 Although it showed short-term variations, it
was maintained very close to the target over a longer
duration.42 The incidences of hypoxemia, hypocarbia, and
hypercarbia were also lower in HFOV þ VG than in HFOV
alone, which might be attributed to the diminished fluctuations in SpO2 and CO2 clearance.41,43 High-frequency
ventilation is more suitable for infants with low lung
compliance and HFOV þ VG can help preterm infants with
RDS acquire adequate ventilation in the first 72 h using a
low-volume and high-frequency strategy.44
HFOV þ VG ventilation enables the delivery of low tidal
volumes and stabilizes the partial pressure of carbon dioxide with good compensation of endotracheal tube leak.44
However, VG ventilation is not recommended in the presence of a large leak. Leaks of more than 40% might underestimate the delivered tidal volumes and trigger a low
tidal volume alarm, thereby diminishing the accuracy and
reliability of VG ventilation.
6. Aerosolized drug delivery
In addition to respiratory support, preterm infants may
require pharmacological interventions to treat comorbidities associated with lung immaturity. Aerosol delivery is
primarily performed via the nasal route in newborn infants,
since they are primarily nasal breathers. Preterm infants
have a smaller tidal volume, higher breathing frequency,
and shorter inhalation time compared to term infants,
resulting in reduced aerosol delivery and residence time in
the lungs. In addition, lung pathologies, such as RDS, limit
aerosol medication in preterm infants. Surprisingly, preterm
344
Pediatrics and Neonatology 63 (2022) 341e347
spread dramatically since December 2019, resulting in a
global pandemic.56 Pediatric patients seem to exhibit fewer
clinical symptoms, which makes it challenging to identify
this disease in children. Most of the newborn infants with
negative test results or those not tested for the disease
were asymptomatic after birth. The potential harm caused
by SARS-CoV-2 infection to neonates is still unknown,
particularly in preterm infants. SARS-CoV-2 immunoglobulin
and inflammatory cytokine interleukin-6 have been detected in the serum obtained within 2 h of birth from some
neonates whose mothers had a SARS-CoV-2 infection,57
suggesting the possibility of intrauterine transmission.
Maternal infection can contribute to birth asphyxia and
prematurity.58 Prematurity, lung injury, and other morbidities in preterm infants may increase the risk of COVID-19.
A study suggested that adult patients with COVID-19
responded better to NIV than to mechanical ventilation
when they progressed to a stage similar to surfactantdeficient RDS that extensive alveolar collapse caused hypoxemia.59 Despite the benefits of early administration of
exogenous surfactants in infants with RDS, it is unclear
whether it can reduce the severity and improve the
deposition in the lung. However, a delay is inevitable when
a nebulizer is used with an NIV circuit.52 NIV ideally delivers
heated and humidified gas to preterm infants and the humidity in the NIV circuits reduces drug delivery by 40%,
probably by increasing the particle size.53
Wastage of drugs during exhalation is the main disadvantage of aerosol therapy involving continuous drug delivery. Recent development of nasal prongs with integrated
miniaturized aerosol valves allows breath-triggered drug
release during inhalation with an aerosol valve response
time <25 ms. The efficiency of aerosol delivery in breathtriggered release was four times higher than that in nontriggered release.54 Breath-triggered drug release during
different phases of inspiration can target different lung
regions, reducing drug distribution in the body.55
7. Recent challenges in neonatal respiratory
care during the coronavirus disease 2019
pandemic
The coronavirus disease 2019 (COVID-19) caused by severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has
Figure 1
Brief summary of the benefits of current respiratory strategies for infants.
345
I.-L. Chen and H.-L. Chen
outcomes of COVID-19. NIV is considered safe in neonates if
applied with proper infection-control measures, tight
fitting of the interface, and viral filters that prevent the
dispersion of infected aerosols.60 However, more evidence
is required to support and confirm the safety of respiratory
practices in neonates with COVID-19.
intermittent positive pressure ventilation versus nasal CPAP after
extubation of VLBW infants. Neonatology 2020;117:193e9.
11. Ding F, Zhang J, Zhang W, Zhao Q, Cheng Z, Wang Y, et al.
Clinical study of different modes of non-invasive ventilation
treatment in preterm infants with respiratory distress syndrome after extubation. Front Pediatr 2020;8:63.
12. Gizzi C, Montecchia F, Panetta V, Castellano C, Mariani C,
Campelli M, et al. Is synchronised NIPPV more effective than
NIPPV and NCPAP in treating apnoea of prematurity (AOP)? A
randomised cross-over trial. Arch Dis Child Fetal Neonatal Ed
2015;100:F17e23.
13. Aghai ZH, Saslow JG, Nakhla T, Milcarek B, Hart J, LawryshPlunkett R, et al. Synchronized nasal intermittent positive
pressure ventilation (SNIPPV) decreases work of breathing
(WOB) in premature infants with respiratory distress syndrome
(RDS) compared to nasal continuous positive airway pressure
(NCPAP). Pediatr Pulmonol 2006;41:875e81.
14. Huang L, Mendler MR, Waitz M, Schmid M, Hassan MA,
Hummler HD. Effects of synchronization during noninvasive
intermittent mandatory ventilation in preterm infants with
respiratory distress syndrome immediately after extubation.
Neonatology 2015;108:108e14.
15. Handoka NM, Azzam M, Gobarah A. Predictors of early synchronized non-invasive ventilation failure for infants< 32
weeks of gestational age with respiratory distress syndrome.
Arch Med Sci 2019;15:680e7.
16. Salvo V, Lista G, Lupo E, Ricotti A, Zimmermann LJI,
Gavilanes AWD, et al. Comparison of three non-invasive
ventilation strategies (NSIPPV/BiPAP/NCPAP) for RDS in VLBW
infants. J Matern Fetal Neonatal Med 2018;31:2832e8.
17. Buyuktiryaki M, Okur N, Sari FN, Ozer Bekmez B,
Bezirganoglu H, Cakir U, et al. Comparison of three different
noninvasive ventilation strategies as initial respiratory support
in very low birth weight infants with respiratory distress syndrome: a retrospective study. Arch Pediatr 2020;27:322e7.
18. Pan R, Chen GY, Wang J, Zhou ZX, Zhang PY, Chang LW, et al.
Bi-level nasal positive airway pressure (BiPAP) versus nasal
continuous positive airway pressure (CPAP) for preterm infants
with birth weight less than 1500 g and respiratory distress
syndrome following INSURE treatment: a two-center randomized controlled trial. Curr Med Sci 2021;41:542e7.
19. Mukerji A, Abdul Wahab MG, Razak A, Rempel E, Patel W,
Mondal T, et al. High CPAP vs. NIPPV in preterm neonatesda
physiological cross-over study. J Perinatol 2021;41:1690e6.
20. Ahmad HA, Deekonda V, Patel W, Thabane L, Shah PS,
Mukerji A. Comparison of high CPAP versus NIPPV in preterm
neonates: a retrospective cohort study. Am J Perinatol 2021.
https://doi.org/10.1055/s-0041-1727159.
21. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB.
Nasal CPAP or intubation at birth for very preterm infants.
N Engl J Med 2008;358:700e8.
22. Martherus T, Oberthuer A, Dekker J, Kirchgaessner C, van
Geloven N, Hooper SB, et al. Comparison of two respiratory
support strategies for stabilization of very preterm infants at
birth: a matched-pairs analysis. Front Pediatr 2019;7:3.
23. Uchiyama A, Okazaki K, Kondo M, Oka S, Motojima Y, Namba F,
et al. Randomized controlled trial of high-flow nasal cannula in
preterm infants after extubation. Pediatrics 2020;146:
e20201101.
24. Hong H, Li XX, Li J, Zhang ZQ. High-flow nasal cannula versus
nasal continuous positive airway pressure for respiratory support in preterm infants: a meta-analysis of randomized
controlled trials. J Matern Fetal Neonatal Med 2021;34:
259e66.
25. Radicioni M, Leonardi A, Lanciotti L, Rinaldi VE, Bini V,
Camerini PG. How to improve CPAP failure prediction in preterm infants with RDS: a pilot study. Eur J Pediatr 2021;180:
709e16.
8. Conclusion
RDS is a major cause of invasive ventilation in neonates.
Although lung immaturity mainly contributes to long-term
morbidity in preterm infants, ventilator-induced lung injury
is also recognized as a key factor in the development of BPD.
Fig. 1 summarizes the benefits of current respiratory strategies for infants. It is challenging but crucial for clinicians
to use appropriate respiratory strategies in neonates, not
only to save their lives but also to ensure better short-term
and long-term outcomes.
Declaration of competing interest
The authors have no conflicts of interest relevant to this
article.
References
1. Soll R. Synthetic surfactant for respiratory distress syndrome in
preterm infants. Cochrane Database Syst Rev 2000;1998:
CD001149.
2. Brix N, Sellmer A, Jensen MS, Pedersen LV, Henriksen TB. Predictors for an unsuccessful INtubation-SURfactant-Extubation
procedure: a cohort study. BMC Pediatr 2014;14:155.
3. De Bisschop B, Derriks F, Cools F. Early predictors for
intubation-surfactant-extubation failure in preterm infants
with neonatal respiratory distress syndrome: a systematic review. Neonatology 2020;117:33e45.
4. Rigo V, Lefebvre C, Broux I. Surfactant instillation in spontaneously breathing preterm infants: a systematic review and
meta-analysis. Eur J Pediatr 2016;175:1933e42.
5. Lau CSM, Chamberlain RS, Sun S. Less invasive surfactant
administration reduces the need for mechanical ventilation in
preterm infants: a meta-analysis. Glob Pediatr Health 2017;4.
2333794X17696683.
6. Langhammer K, Roth B, Kribs A, Göpel W, Kuntz L, Miedaner F.
Treatment and outcome data of very low birth weight infants
treated with less invasive surfactant administration in comparison to intubation and mechanical ventilation in the clinical
setting of a cross-sectional observational multicenter study.
Eur J Pediatr 2018;177:1207e17.
7. Herting E, Kribs A, Härtel C, von der Wense A, Weller U,
Hoehn T, et al. Two-year outcome data suggest that less invasive
surfactant administration (LISA) is safe. Results from the followup of the randomized controlled AMV (avoid mechanical ventilation) study. Eur J Pediatr 2020;179:1309e13.
8. Klotz D, Porcaro U, Fleck T, Fuchs H. European perspective on
less invasive surfactant administrationda survey. Eur J Pediatr
2017;176:147e54.
9. Dekker J, Lopriore E, Van Zanten HA, Tan RNGB, Hooper SB, Te
Pas AB. Sedation during minimal invasive surfactant therapy: a
randomised controlled trial. Arch Dis Child Fetal Neonatal Ed
2019;104:F378e83.
10. Estay AS, Mariani GL, Alvarez CA, Milet B, Agost D, Avila CP, et al.
Randomized controlled trial of nonsynchronized nasal
346
Pediatrics and Neonatology 63 (2022) 341e347
43. Enomoto M, Keszler M, Sakuma M, Kikuchi S, Katayama Y,
Takei A, et al. Effect of volume guarantee in preterm infants
on high-frequency oscillatory ventilation: a pilot study. Am J
Perinatol 2017;34:26e30.
44. Solı́s-Garcı́a G, González-Pacheco N, Ramos-Navarro C, Rodrı́guez Sánchez de la Blanca A, Sánchez-Luna M. Target volumeguarantee in high-frequency oscillatory ventilation for preterm
respiratory distress syndrome: low volumes and high frequencies lead to adequate ventilation. Pediatr Pulmonol 2021;
56:2597e603.
45. Clark AR. Essentials for aerosol delivery to term and pre-term
infants. Ann Transl Med 2021;9:594.
46. Köhler E, Jilg G, Avenarius S, Jorch G. Lung deposition after
inhalation with various nebulisers in preterm infants. Arch Dis
Child Fetal Neonatal Ed 2008;93:F275e9.
47. Sunbul FS, Fink JB, Harwood R, Sheard MM, Zimmerman RD,
Ari A. Comparison of HFNC, bubble CPAP and SiPAP on aerosol
delivery in neonates: an in-vitro study. Pediatr Pulmonol 2015;
50:1099e106.
48. Sood BG, Cortez J, Kolli M, Sharma A, Delaney-Black V, Chen X.
Aerosolized surfactant in neonatal respiratory distress syndrome: phase I study. Early Hum Dev 2019;134:19e25.
49. Bass K, Boc S, Hindle M, Dodson K, Longest W. High-efficiency
nose-to-lung aerosol delivery in an infant: development of a
validated computational fluid dynamics method. J Aerosol Med
Pulm Drug Deliv 2019;32:132e48.
50. Li J, Gong L, Ari A, Fink JB. Decrease the flow setting to
improve trans-nasal pulmonary aerosol delivery via “high-flow
nasal cannula” to infants and toddlers. Pediatr Pulmonol 2019;
54:914e21.
51. Kesavan S, Amirav I. Is aerosol delivery by high-flow nasal cannula in children an effective alternative to face mask aerosol
nebulization? Pediatr Pulmonol 2019; Dec;54:1873e1874.
52. Aerogen. Aerogen solo system instruction manual. 2020. Available at https://www.aerogen.com/wp-content/uploads/2020/
09/30-674-Rev-L-Aerogen-Solo-System-Instruction-Manual-US_
WEB.pdf. Accessed September 26, 2021.
53. Longest PW, Tian G, Hindle M. Improving the lung delivery of
nasally administered aerosols during noninvasive ventilationdan application of enhanced condensational growth
(ECG). J Aerosol Med Pulm Drug Deliv 2011;24:103e18.
54. Wiegandt FC, Froriep UP, Müller F, Doll T, Dietzel A,
Pohlmann G. Breath-Triggered Drug Release System for Preterm Neonates. Pharmaceutics 2021;13:657.
55. Martin AR. Regional deposition: Targeting. J Aerosol Med Pulm
Drug Deliv 2021;34:1e10.
56. Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiology of
COVID-19 among children in China. Pediatrics 2020;145:
e20200702.
57. Zeng H, Xu C, Fan J, Tang Y, Deng Q, Zhang W, et al. Antibodies
in infants born to mothers with COVID-19 pneumonia. JAMA
2020;323:1848e9.
58. Dhillon SK, Lear CA, Galinsky R, Wassink G, Davidson JO, Juul S,
et al. The fetus at the tipping point: modifying the outcome of
fetal asphyxia. J Physiol 2018;596:5571e92.
59. Koumbourlis AC, Motoyama EK. Lung mechanics in COVID-19
resemble respiratory distress syndrome, not acute respiratory
distress syndrome: could surfactant be a treatment? Am J
Respir Crit Care Med 2020;202:624e6.
60. Shalish W, Lakshminrusimha S, Manzoni P, Keszler M,
Sant’Anna GM. COVID-19 and neonatal respiratory care: current evidence and practical approach. Am J Perinatol 2020;37:
780e91.
26. Garcı́a-Muñoz Rodrigo F, Urquı́a Martı́ L, Galán Henrı́quez G, Rivero
Rodrı́guez S, Hernández Gómez A. Neural breathing patterns in
preterm newborns supported with non-invasive neurally adjusted
ventilatory assist. J Perinatol 2018;38:1235e41.
27. Ducharme-Crevier L, Beck J, Essouri S, Jouvet P, Emeriaud G.
Neurally adjusted ventilatory assist (NAVA) allows patientventilator synchrony during pediatric noninvasive ventilation:
a crossover physiological study. Crit Care 2015;19:44.
28. Gibu CK, Cheng PY, Ward RJ, Castro B, Heldt GP. Feasibility and
physiological effects of noninvasive neurally adjusted ventilatory assist in preterm infants. Pediatr Res 2017;82:650e7.
29. Matlock DN, Bai S, Weisner MD, Comtois N, Beck J, Sinderby C,
et al. Work of breathing in premature neonates: noninvasive
neurally-adjusted ventilatory assist versus noninvasive ventilation. Respir Care 2020;65:946e53.
30. Lee J, Kim HS, Jung YH, Shin SH, Choi CW, Kim EK, et al. Noninvasive neurally adjusted ventilatory assist in preterm infants:
a randomised phase II crossover trial. Arch Dis Child Fetal
Neonatal Ed 2015;100:F507e13.
31. Baudin F, Emeriaud G, Essouri S, Beck J, Javouhey E, Guerin C.
Neurally adjusted ventilatory assist decreases work of
breathing during non-invasive ventilation in infants with severe
bronchiolitis. Crit Care 2019;23:120.
32. Tabacaru CR, Moores Jr RR, Khoury J, Rozycki HJ. NAVA
dsynchronized compared to nonsynchronized noninvasive
ventilation for apnea, bradycardia, and desaturation events in
VLBW infants. Pediatr Pulmonol 2019;54:1742e6.
33. Firestone K, Horany BA, de Leon-Belden L, Stein H. Nasal
continuous positive airway pressure versus noninvasive NAVA in
preterm neonates with apnea of prematurity: a pilot study
with a novel approach. J Perinatol 2020;40:1211e5.
34. Firestone KS, Fisher S, Reddy S, White DB, Stein HM. Effect of
changing NAVA levels on peak inspiratory pressures and electrical
activity of the diaphragm in premature neonates. J Perinatol
2015;35:612e6.
35. Kallio M, Koskela U, Peltoniemi O, Kontiokari T, Pokka T, SuoPalosaari M, et al. Neurally adjusted ventilatory assist (NAVA)
in preterm newborn infants with respiratory distress syndromea randomized controlled trial. Eur J Pediatr 2016;175:
1175e83.
36. Lefevere J, Van Delft B, Vervoort M, Cools W, Cools F. Non-invasive
neurally adjusted ventilatory assist in preterm infants with RDS:
effect of changing NAVA levels. Eur J Pediatr 2021;181:701e7.
37. Duman N, Tuzun F, Sutcuoglu S, Yesilirmak CD, Kumral A,
Ozkan H. Impact of volume guarantee on synchronized ventilation in preterm infants: a randomized controlled trial.
Intensive Care Med 2012;38:1358e64.
38. Keszler M, Abubakar K. Volume guarantee: stability of tidal
volume and incidence of hypocarbia. Pediatr Pulmonol 2004;
38:240e5.
39. Unal S, Ergenekon E, Aktas S, Altuntas N, Beken S, Kazanci E, et al.
Effects of volume guaranteed ventilation combined with two
different modes in preterm infants. Respir Care 2017;62:1525e32.
40. Alkan Ozdemir S, Arun Ozer E, Ilhan O, Sutcuoglu S. Impact of
targeted-volume ventilation on pulmonary dynamics in preterm infants with respiratory distress syndrome. Pediatr Pulmonol 2017;52:213e6.
41. Iscan B, Duman N, Tuzun F, Kumral A, Ozkan H. Impact of
volume guarantee on high-frequency oscillatory ventilation in
preterm infants: a randomized crossover clinical trial. Neonatology 2015;108:277e82.
42. Belteki G, Morley CJ. High-frequency oscillatory ventilation
with volume guarantee: a single-centre experience. Arch Dis
Child Fetal Neonatal Ed 2019;104:F384e9.
347