Received: 18 July 2017 | Accepted: 21 July 2017
DOI: 10.1002/ppul.23784
EDITORIAL
Non-invasive high-frequency oscillatory ventilation for
preterm newborns: The time has come for consideration
Endotracheal mechanical ventilation in preterm infants is a major risk
factor for bronchopulmonary dysplasia (BPD) via ventilator-induced
lung injury.1 Randomized clinical trials (RCT) have shown that the use
of nasal continuous positive airway pressure (nCPAP) at birth
decreases the need for endotracheal mechanical ventilation, as well
2,3
as death or BPD. Most preterm infants are now managed by nCPAP
at birth and are never intubated. Surfactant administration, if needed,
is performed via transient tracheal intubation or through a small
endotracheal catheter without intubation (LISA or MIST procedure).4
Unfortunately, studies have shown a high rate of nCPAP failure in the
most premature newborns (22-26 weeks’ gestational age),2,3 who have
a distressing incidence of BPD.5 Consequently, in recent years, various
non-invasive respiratory support modalities have been developed with
the hope of preventing endotracheal mechanical ventilation and BPD.
As a result, heated humidified high-flow nasal cannula and various
forms of synchronized intermittent positive pressure ventilation,
among others, have drawn considerable attention.2,3,6
Non-invasive high-frequency oscillatory ventilation (NHFOV) is a
new and exciting strategy that could redefine respiratory support of
the preterm infant. Theoretical reasons for using NHFOV, as well as a
number of case reports and observational studies reporting positive
effects in human neonates and animal models, have been the focus of
recent reviews.7–9 NHFOV is viewed as a gentler method of delivering
mechanical ventilation. It has the advantages of both high-frequency
ventilation, that is, absence of ventilator-patient asynchrony and high
efficacy in removing CO2, and non-invasive CPAP, including among
others, an improved oxygenation via an increased functional residual
capacity. Recent surveys in Europe and Canada have shown that a
significant number of NICUs have already included this strategy in their
10,11 8
therapeutic armamentarium, at times on a regular basis. The lack
of RCT is however a big concern.
The first ever (pilot) RCT on NHFOV was performed in full-term
newborns with transient tachypnea. Results showed a reduced
12
duration of respiratory distress and oxygen supplementation. Of
probable greater clinical relevance is a recent parallel-arm, RCT
comparing NHFOV versus biphasic nCPAP (control group) as a rescue
therapy following failure of nCPAP in preterm infants born at a mean
13
gestational age of 26 weeks. Mean postmenstrual age at the time of
the study was around 29 weeks. The primary aim of this pilot RCT
conducted in a low number of infants (17 in the NHFOV group and 23
in the biphasic nCPAP group) was to show the feasibility of a future,
adequately powered RCT. While feasibility was shown, no positive
1526 | © 2017 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/ppul
effect on the need for endotracheal mechanical ventilation could
nonetheless be found.
In this issue of Pediatric Pulmonology, Zhu et al14 report the results
of an unblinded RCT on NHFOV as the initial respiratory support for
preterm infants. The authors compared the efficacy of nasal HFOV
versus nasal CPAP (control group) in preventing the need for
endotracheal intubation in preterm infants with moderate to severe
respiratory distress syndrome at birth after surfactant administration
via the INSURE (INtubation, SURfactant, Extubation) method. Eighty-
one preterm infants, with a gestational age of 28-34 weeks (mean
gestational age ∼ 32 weeks), were randomized into NHFOV and
nCPAP groups. NHFOV was delivered by binasal prongs with a mean
airway pressure of 6-10 cmH2O and an oscillation frequency of
6-12 Hz, while nCPAP was “started at 6 cmH2O” in control infants.
Results showed that the need for endotracheal mechanical ventilation
was more than halved (24.3% vs 56.4%, P = 0.004) in the NHFOV
group without increased adverse effects compared to nCPAP. The
incidence of BPD (as defined by the NIH consensus in 2000),15
however, was not significantly decreased in the NHFOV group.
The absence of a significant effect on BPD incidence may seem at
odds with the positive effects of NHFOV previously reported in a
preterm lamb model of BPD. In these latter studies, NHFOV resulted in
better gas exchange, reduced lung injury and improved alveolar
formation and weight gain (another key factor for BPD prevention16),
compared to endotracheal pressure-limited, volume-targeted
8,17,18
mechanical ventilation. Beyond potential species differences,
other explanations could account for the absence of positive effect on
BPD incidence in the study by Zhu et al. First, on top of a relatively
small number of preterm newborns studied, the BPD incidence was
low in the control group, as expected for preterm infants born at 32
weeks’ gestational age. This low incidence in control newborns greatly
hinders the possibility of showing a positive effect of any intervention.
In addition, while newborns in the control group were treated by non-
invasive bubble CPAP, previous comparison in preterm lambs were
performed between NHFOV and endotracheal ventilation, which in
itself is a major risk factor for BPD. Moreover, the presence of high
frequency oscillations (between 15 and 30 Hz), which is inherent to
bubble CPAP,19,20 may have reduced the difference between the
nHFOV and control groups in the study by Zhu et al.
Further limitations of the study are significant. First and foremost,
the study was performed in moderately preterm infants (mean
gestational age of 32 weeks), leaving unanswered the question of a
Pediatric Pulmonology. 2017;52:1526–1528.
PRAUD AND FORTIN-PELLERIN
positive effect of NHFOV in the most premature newborns, who are
1,5
the ones at risk for severe BPD. In addition, Zhu et al report an
unexpectedly high incidence of endotracheal intubation in the control
group (56%) for moderately preterm infants.2,3 Furthermore, although
the authors used a definition of BPD that was well accepted until
recently,15 its adequacy is now being disputed by a number of
experts.1,21–24 Indeed, as already alluded to, nCPAP or heated
humidified high-flow nasal cannula is frequently used beyond 36 weeks
postconceptional age without oxygen supplementation. Comparing
the percentage of infants at 36 weeks postconceptional age with
oxygen supplementation and/or respiratory support (including heated
humidified high-flow nasal cannula) would have been more adequate.
Finally, analyzing additional secondary relevant outcomes, such as
late-onset sepsis, necrotizing enterocolitis or retinopathy of prematu-
rity, was unfortunately precluded by their limited sample size in the
moderately preterm infants under study.5
Many further questions remain with regard to the use of NHFOV in
infants, whether in the preterm newborn or beyond the neonatal period.
As recently underlined, although various ventilators can deliver nHFOV,
they are nonetheless not equivalent.8 For instance, the possibility with
some ventilators to deliver tidal volumes at low frequency in addition to
high-frequency oscillations may be a significant asset.8 In addition, the
optimal non-invasive interface to be used to deliver NHFOV remains
unclear. While nasal/oronasal masks, nasopharyngeal tube, and nasal
cannulae have all been successfully used to deliver NHFOV,7,8,25 the
dampening of oscillations,25 or the presence of leaks26 have a significant
effect on lung ventilation. Moreover, while the range of oscillation
frequencies used previously is 6-14 Hz, the optimal frequency remains
unclear and may vary depending on the ventilator, the interface, the
presence of leaks, the patient and the aim of NHFOV. For instance,
decreasing oscillation frequency from 8 to 4 Hz led to the appearance of
prolonged central apneas (several minutes duration) with normal blood
gases in non-sedated lambs.27
Future RCT will need to test other potential indications of NHFOV
in preterm newborns. This includes the use of NHFOV as the initial
method of non-invasive respiratory support at birth or as a rescue
treatment when other methods of non-invasive respiratory support fail
or to facilitate weaning from endotracheal ventilation.28 Of high
interest as well for pediatric pulmonologists is the potential use of
NHFOV beyond the neonatal period. In this regard, a proof of principle
study has shown that NHFOV is feasible and safe in one-year old
infants.25 Also, NHFOV has been successfully used in one infant with
very severe respiratory acidosis (pH = 6.97, PCO2 = 148 mmHg) due to
acute viral bronchiolitis.29 As previously underlined,30 these two
reports, while anecdotal, open the door to the use of NHFOV beyond
the neonatal period. Finally, an intriguing report in non-sedated adults
has taken advantage of the ability of NHFOV to induce prolonged
central apneas in order to perform higher quality lung images or deliver
radiotherapy at lower doses.31
In conclusion, Zhu et al must be congratulated for showing for the
first time that nHFOV, when used as an initial respiratory support in
moderately preterm newborns with respiratory distress, can decrease
the need for endotracheal ventilation. There is now an urgent need to
| 1527
confirm the positive effect of NHFOV in the most premature
newborns in the hope of alleviating the distressing burden of severe
BPD in this population.
Jean-Paul Praud
Étienne Fortin-Pellerin
Divisions of Respiratory Medicine and Neonatology,
Department of Pediatrics, University of Sherbrooke,
Quebec, Canada
Correspondence
Jean-Paul Praud, MD, PhD, Departments of Pediatrics and
Pharmacology − Physiology,
Université de Sherbrooke, QC, Canada, J1H 5N4.
Email: jean-paul.praud@USherbrooke.ca
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