Physiologic Effect of High-Flow Nasal Cannula in
Infants With Bronchiolitis
Judith L. Hough, PhD1,2,3; Trang M. T. Pham, BEng1; Andreas Schibler, MD, FCICM1
Objective: To assess the effect of delivering high-flow nasal can-
nula flow on end-expiratory lung volume, continuous distending
pressure, and regional ventilation distribution in infants less than
12 months old with bronchiolitis.
Design: Prospective observational clinical study.
Setting: Nineteen bed medical and surgical PICU.
Patients: Thirteen infants with bronchiolitis on high-flow nasal therapy.
Interventions: The study infants were measured on a flow rate
applied at 2 and 8 L/min through the high-flow nasal cannula system.
Measurements and Results: Ventilation distribution was measured
with regional electrical impedance amplitudes and end-expiratory
lung volume using electrical impedance tomography. Changes in
continuous distending pressure were measured from the esophagus
via the nasogastric tube. Physiological variables were also recorded.
High-flow nasal cannula delivered at 8 L/min resulted in signifi-
cant increases in global and anterior end-expiratory lung volume
(p < 0.01) and improvements in the physiological variables of respi-
ratory rate, Spo2, and Fio2 when compared with flows of 2 L/min.
Conclusion: In infants with bronchiolitis, high-flow nasal cannula
oxygen/air delivered at 8 L/min resulted in increases in end-expi-
ratory lung volume and improved respiratory rate, Fio2, and Spo2.
(Pediatr Crit Care Med 2014; 15:e214–e219)
Key Words: continuous positive airways pressure; electrical
impedance tomography; high-flow nasal cannula; oxygen delivery;
ventilation distribution
B
ronchiolitis is the leading cause of pediatric hospital-
ization in Australia and New Zealand and accounts for
approximately 8,000 admissions annually (1). Respi-
ratory support is fundamental to the treatment of severe
1
Paediatric Critical Care Research Group, Paediatric Intensive Care Unit,
Mater Children’s Hospital, South Brisbane, QLD, Australia.
2
School of Physiotherapy, Australian Catholic University, Banyo, QLD, Australia.
3
Critical Care of the Newborn Program, Mater Research, South Brisbane,
QLD, Australia.
Dr. Schibler’s institution received grant support from Fisher & Paykel
Healthcare. The remaining authors have disclosed that they do not have
any potential conflicts of interest.
For information regarding this article, E-mail: judith.hough@mater.org.au
Copyright © 2014 by the Society of Critical Care Medicine and the World
Federation of Pediatric Intensive and Critical Care Societies
DOI: 10.1097/PCC.0000000000000112
e214 www.pccmjournal.org June 2014 • Volume 15 • Number 5
bronchiolitis, and various forms of noninvasive respiratory
therapy have been used in its treatment (2). Continuous posi-
tive airways pressure (CPAP) has been used to decrease the
work of breathing, improve functional residual capacity, and
reduce regional atelectasis associated with this disease (3, 4).
CPAP can be delivered via nasopharyngeal tube or face mask
and generated by a water column (bubble CPAP) or a dedi-
cated CPAP driver (5). Despite the acknowledged clinical use-
fulness of nasal CPAP, uncertainties regarding aspects of its
application remain. Furthermore, defining the optimal nasal
CPAP system is complicated by the multiplicity of nasal CPAP
devices and techniques available to the clinician (6).
Recently high-flow nasal cannula (HFNC) therapy has been
introduced to provide respiratory support in infants (7–9).
HFNC is considered to be the delivery of gas flow rates exceeding
2 L/min. HFNC therapy has many possible advantages over other
forms of oxygen therapy: the inspired gas mixture can be heated
and humidified to reduce damage to the upper airway mucosa;
the inspired oxygen concentration can be titrated to the patients
need; anecdotally, it is better tolerated by the patient; and poten-
tially, CPAP can be delivered (10–13). Studies in neonates have
shown that the amount of CPAP delivered by HFNC depends
on the flow (relative to the size of the patient) and on the leak
around the nasal cannula (14). Most studies of HFNC therapy
have been performed in neonates, and little clinical experience is
reported in older children (7). A number of studies have investi-
gated the effect of HFNC in treating apnoea of prematurity (15),
on the CPAP effect in neonates (14, 16), pharyngeal pressure
(12), and its role in the postextubation period (8, 17, 18). Despite
its acceptance, the use of HFNC is still controversial and not rec-
ommended by some outside of a research protocol (19–22). Of
primary concern is the paucity of available evidence on the effect
of HFNC on CPAP and end-expiratory lung volume (EELV).
The purpose of this study was to investigate the effect of HFNC
flow on CPAP, EELV, regional ventilation distribution, and other
respiratory physiological variables in infants with bronchiolitis.
METHODS
Study Design
In a prospective interventional study, infants with bronchiolitis
were measured on and off HFNC.

Subjects
Infants with the diagnosis of bronchiolitis were recruited from
the PICU at the Mater Children’s Hospital, South Brisbane, Aus-
tralia. Criteria for admission to PICU were an oxygen require-
ment of more than 2 L/min to maintain Spo2 more than 94%
and the need for respiratory support due to increased work of
breathing. Inclusion criteria for the study were infants less than
12 months old who were placed on HFNC respiratory support
for respiratory distress due to a viral bronchiolitis (confirmed
with a positive polymerase chain reaction test for viral infec-
tion in the nasopharyngeal aspirate) and who had a nasogastric
(NG) feeding tube in place. Exclusion criteria were an oxy-
gen requirement of more than 60%, structural upper airway
obstruction, or craniofacial malformation. The study protocol
was approved by the Human Research Ethics Committee of the
Mater Health Services, South Brisbane, Queensland. Informed
written consent was obtained from the parents.
HFNC System
The Fisher & Paykel humidified high-flow system was used
with a low resistance pediatric binasal cannula (BC3780 and
RT329; Fisher & Paykel Healthcare, Auckland, New Zealand).
Inspired oxygen concentration was titrated to achieve pulse
oximeter oxygen saturations (Spo2) between 94% and 98%.
The flow rate used was set at 8 L/min (equipment limitation)
at the beginning of the HFNC treatment.
The study infants were measured on a flow rate applied at 2 or
8 L/min through the HFNC system with the order of the applied
flow rate randomized. A period of at least 5 minutes was allowed
to stabilize before taking measurements over a 3-minute period.
At the conclusion of the study, infants were placed back on their
prestudy flow rate of 8 L/min for ongoing treatment. All infants
were nursed in the supine position throughout the study.
Measurements
Electrical impedance tomography (EIT) data allow measure-
ment of change in end-expiratory level (or lung volume, EELV)
and changes in regional ventilation distribution or regional
tidal volume changes in spontaneously breathing subjects with-
out interfering with normal breathing. The principle of EIT is
based on the rapid cyclic acquisition of potential differences on
the surface of the chest produced by repetitive injections of a
small electrical current. Both the voltages and current are mea-
sured between pairs of 16 conventional electrodes (Kendall,
Kittycat 1050NPSM; Tyco Healthcare group, Mansfield, MA)
placed circumferentially around the chest at nipple level. EIT
scans are generated from the collected potential differences and
the known excitation currents using weighted back-projection
in a 32 × 32 pixel matrix (23). Each pixel represents the instan-
taneous relative local impedance change relative to baseline.
The majority of the measured impedance change is caused by
local air volume change, and hence, the measured impedance
change of each pixel correlates closely to local (tidal) volume
change (24). In summary, EIT allows measuring change of
lung volume (comparable to functional residual capacity mea-
surements) and measuring regional tidal breathing.
Pediatric Critical Care Medicine www.pccmjournal.org e215
Online Clinical Investigations
A Gottingen GoeMF II tomograph (VIASYS Healthcare,
Houten, The Netherlands) was used. Three-minute measurements
were taken at 2 and 8 L/min flow rates. Software provided with
the equipment was used for data acquisition and reconstruction
of functional relative EIT images (25). Data were further analyzed
off-line using Matlab 7.7 (R2008b; The MathWorks, Natick, MA).
Data Processing and Analysis
EIT data were band-pass filtered to include the first and second
harmonic of the respiratory rate (26). A cutoff mask of 20% of
the peak impedance signal was applied (27) to reduce cardiac
interference (28). Regular sections of data were selected for analy-
sis. The following criteria were used to select these periods (29).
1 . Length of 3–5 breaths
2. Regular breathing rate
3. Stable tidal volume and EELV
4. Rejection of the first breath if a respiratory pause preceded
the tidal breathing period
Measurement of End-Expiratory Level and Regional
Ventilation Distribution
Changes in EELV at 2 L/min were compared with 8 L/min flow
rates for the global, the dependent (posterior), and nondepen-
dent (anterior) lung. An example of global EELV change with
a switch from “off HFNC” to “on HFNC” is shown in F ­ igure 1.
Regional impedance amplitudes were used to describe the
magnitude of the regional tidal volume change within an
individual over time. Impedance amplitudes for the global,
the dependent (posterior), and nondependent (anterior) lung
were calculated by averaging the impedance differences in each
pixel of the measurement period between the end-expiratory
and end-inspiratory periods. To account for the unequal num-
ber of pixels analyzed in each region of interest (ROI), the aver-
age amplitude for each ROI was reported.
A global inhomogeneity (GI) index was also calculated
for the entire lung region using a tidal EIT image of the end-
expiration to end-inspiration differences of the EIT impedance
signal of each image pixel. The GI index is used as an indica-
tor of inhomogeneous ventilation by describing variations in
the pixel values of the tidal EIT image (30). The higher the GI
value the more ventilation inhomogeneity exists.
Measurement of Esophageal Pressure
Esophageal pressure (Poe) measurements were taken as an indi-
cation of CPAP. To achieve this measurement, the NG tube was
connected to a pressure transducer and the in situ NG feeding
tube was pulled back to the distal third of the esophagus where
it was positioned to achieve a waveform in the range of –5 to 5
kPa that was free from cardiac artifact (31). Feeds were discon-
tinued for the length of the study. To maintain patency of the
NG tube, it was flushed with normal saline at a rate of 1 mL/hr.
Mouth closure was required for measurements, either spontane-
ously or with a pacifier. The pressure signal was connected into
the EIT equipment to synchronize the signals. Poe was measured
at 2 and 8 L/min and measures taken at end inspiration and end
expiration. Additionally, we calculated the pressure rate product
Hough et al

any equipment adjustment dis-

turbed the breathing pattern
of the subject and the quality
of the signals. The successfully
measured infants had a mean
(± sd) age of 3.17 months (± 2.06
mo) and a mean study weight
of 4.76 kg (± 1.39 kg), and the
study group consisted of six
female and seven male infants.
HFNC was delivered at an
average rate of 1.7  L/kg/min
(± 0.26 L/kg/min), whereas stan-
dard oxygen delivery at 2 L/min
was equivalent to 0.4 L/kg/min.

Changes in EELV and

Regional Ventilation
Distribution
Changes in EELV at 2  L/min
(off HFNC) were compared
with 8 L/min (on HFNC). An
Figure 1. Illustration of the change in end-expiratory level (EEL) measured with electrical impedance example of global EELV change
tomography on and off high-flow nasal cannula (HFNC). with a switch from off HFNC to
on HFNC is shown in ­Figure 1.
(PRP), which was calculated by multiplying the expiratory pres- The EELV increased significantly on HFNC for the ante-
sure amplitude with the respiratory rate. A decrease in the PRP rior (nondependent) lung (p = 0.017), and there was a trend
indicates a decrease in the work of breathing. toward increased EELV in the posterior and for the global lung,
but the change did not reach a significant level (Fig. 2). Simi-
Measurement of Physiologic Variables larly to the EELV, the global and regional impedance ampli-
Inspired oxygen (Fio2), respiratory rate (RR), heart rate (HR), tudes were higher on HFNC compared with low-flow nasal
and Spo2 were monitored using the Dräger infinity SC800 mon- cannula, but the differences did not reach significance. The GI
itoring system (Dräger Medical AG & Co. KG, Lübeck, Ger- index decreased on HFNC compared with off HFNC indicat-
many) throughout the study. These were manually recorded ing improved ventilation distribution, but the differences did
at the time of each EIT recording. From the collected data, the not reach statistical significance (p = 0.053).
Spo2/Fio2 ratio was calculated (32).
Measurement of Poe
Statistics Poe at end expiration increased significantly from –0.2 ± 7.6 cm
Results are described using mean and ses. After testing for H2O to 6.9 ± 2.1 cm H2O (p = 0.045). Poe at end inspira-
normality (Levene’s test), a paired t test was used to compare tion increased only moderately from –1.9 ± 4.8 cm H2O to
results. A p value of less than 0.05 was considered significant. –0.2 ± 4.8 cm H2O (p = not significant). The PRP decreased
from 1,003 ± 214 to 956 ± 138 (p = 0.14) (Fig. 3).
All statistical analyses were performed using SPSS (v15.0; Lead
Technologies, Chicago, IL).
Changes in Physiologic Variables
It was the original intention to enroll 20 infants based on
RR dropped significantly (p = 0.045) when on HFNC, but there
pilot trials which showed that 1 L/min air flow causes an increase
were no other significant differences in the physiological vari-
of continuous distending pressure (CDP) of 2.8 cm H2O (sd, 2.7;
ables such as HR, Fio2, Sao2, and Sao2/Fio2 on and off HFNC.
n = 9). Using a power of 90% and a p value of less than 0.05, we
There was a tendency for all of these variables to improve with
needed to enroll at least 12 infants. However, due to a change in
HFNC (Table 1).
the circuit available and the unit policy for HFNC use, the study
was forced to discontinue after 13 infants were recruited.
Adverse Events
There were no adverse events recorded during the study period.
RESULTS
Patient Characteristics DISCUSSION
We enrolled 13 patients into the study but could only obtain The main finding of this physiological study was that there were
meaningful EIT and pressure signal readings in 11 infants, as increased end-expiratory Poe associated at HFNC of 8 L/min

e216 www.pccmjournal.org June 2014 • Volume 15 • Number 5

 Online Clinical Investigations

Figure 3. Change in esophageal pressure (Poe) (upper panel) and

pressure rate product (PRP) (lower panel) on and off high-flow nasal
cannula (HFNC). # denotes significant difference for Poe at end expiration
(p < 0.05).

Figure 2. Change of end-expiratory level (EEL) (upper panel) and global

and regional impedance amplitudes (lower panel) measured with electrical information is currently available for spontaneously breathing
impedance tomography on and off high-flow nasal cannula (HFNC). # infants on HFNC. Despite presenting only a small dataset, our
denotes significant difference for the anterior lung (p < 0.05). findings are consistent with previous reports on the physiolog-
ical effect of high flow.
compared with standard flow 2 L/min with a corresponding
increase in EELV in the anterior lung and a decrease in respira- Effect of HFNC on Esophagus Pressure
tory rate. This is the first report documenting a change in EELV We showed that at flow rates of 1.7 L/kg/min, the end-expira-
in infants with bronchiolitis treated with HFNC. One of the tory Poe was significantly higher compared with low-flow oxy-
main difficulties in obtaining accurate lung function data on gen delivery (0.4 L/kg/min). Of particular interest was that the
patients on HFNC therapy is that most techniques cannot be Poe difference between the end-expiratory and end-inspiratory
used while high flow is delivered. Although there are some data phase of the respiratory cycle was much greater on HFNC than
on lung function in ventilated infants with bronchiolitis, little off HFNC (Fig. 3). This effect is best explained with the obser-
vation that during the expiratory phase, the unidirectional
Table 1. Effect of the Flow Rates of 2 and high flow toward the larynx streams against the expiratory flow
8 L/min on Physiological Characteristics of of the patient, creating some resistance and positive pressure.
During the inspiratory phase, however, the unidirectional flow
the Infants: Mean (se) of Each Intervention
of the HFNC is in the same direction as the inspiratory flow of
Intervention the patient, and hence, the observed pressure drops. Although
HFNC increases the expiratory pressure, it differs from CPAP
2 L/min 8 L/min
Outcome (n = 13) (n = 13) during the inspiratory phase. Such differences between inspi-
ratory and expiratory Poe observed during HFNC are not con-
Heart rate (beats/min) 139.9 ± 5.9 134.8 ± 4.5 sistent with the definition of CPAP (continuous positive airway
Respiratory rate (breaths/min) 68.5 ± 6.0 a
56.9 ± 3.2a pressure) but better described as a positive expiratory pressure.
A positive end-inspiratory pressure can only be achieved if the
Spo2 (%) 95.6 ± 0.9 97.3 ± 0.6
flow of the HFNC is greater than the maximal inspiratory flow
Fio2 0.42 ± 0.04 0.34 ± 0.02 of the patient. In our study, we achieved on average 1.7 L/kg/
Spo2/Fio2 251.6 ± 25.9 280.0 ± 20.3 min high flow and an average inspiratory Poe of approximately
a
Respiratory rate decreased significantly on high-flow nasal cannula of 8 L/min
zero. Hence, to achieve some positive pressure during the inspi-
(p = 0.045). ratory phase, even greater flows than 1.7 L/kg/min may need to

Pediatric Critical Care Medicine www.pccmjournal.org e217

Hough et al
be delivered. We estimate that 2 L/kg/min may be an adequate
flow rate, a flow rate that normally has been used in the past to
titrate the circuit flow in a continuous bypass neonatal ventila-
tor. The PRP was only moderately reduced on HFNC, which is
not surprising as the PRP is a composite of pressure amplitude
and respiratory rate. The pressure amplitude as per Figure 3
increased due to the positive end-expiratory pressure effect of
HFNC but the respiratory rate dropped. We may speculate that
the flow rate used in our study was not sufficient to decrease
the work of breathing significantly. This argument may be sup-
ported by the fact that in premature infants, flow rates between
5 and 8 L/min are used to reduce the work of breathing in
babies with a body weight of 1,000 g, which is equivalent to
5–8 L/kg/min. Our results are consistent with measurements
that have recently been published in infants with bronchiolitis
using pharyngeal pressure (33).
Another explanation could be that the higher end-expi-
ratory pressure might be splinting the airways open, helping
to decrease expiratory airflow limitation. There have been a
number of studies investigating the effect of change in air-
way pressure with increasing flow rates and results have var-
ied markedly with no consensus reached and concerns still
related to uncontrolled airway pressure (11, 12, 14, 34–36),
which includes air escaping when the mouth is open. An
increase in airway pressure is only one of the mechanisms
thought to responsible for the positive effects of HFNC.
The variation in results in the literature could be because
there are alternative mechanisms involved. Other proposed
mechanisms include washout of nasopharyngeal dead space,
reduction of inspiratory airflow resistance, improved lung
mechanics, reduced metabolic work required for gas warm-
ing, and humidification (10, 36–38). In situations in which
the flow delivered by the oxygen delivery method is lower
than the maximal inspiratory flow of the patient, then an
air leak around the nasal cannula is needed to entrain air.
Similarly during the expiratory phase, an air leak, either via
mouth or around the nasal cannula, is mandatory. These
leak conditions are absolutely mandatory to be present for
the safe use of HFNC.
Effect of HFNC on EELV
To our knowledge, this is the first study describing changes in
EELV in infants with bronchiolitis and on HFNC. The change in
EELV in our study was moderate but consistent for all patients.
Interestingly, the anterior (nondependent) lung showed the
greatest increase. Bronchiolitis per se is associated with hyper-
inflation and air trapping due to small airway disease. Hence,
any further increase of EELV seems surprising. First, any posi-
tive airway pressure may recruit previously collapsed alveoli;
microatelectasis is one of the main features of bronchiolitis.
The CDP then will splint airway passages helping to mitigate
the effect of expiratory airflow limitation. These findings mir-
ror those found in a cohort of 20 adults who also demonstrated
an increase in global and ventral end-expiratory lung imped-
ance variation when placed on HFNC (39). The global and
regional amplitudes were higher on HFNC compared with
e218 www.pccmjournal.org June 2014 • Volume 15 • Number 5
low-flow nasal cannula. The GI index as a measure of venti-
lation inhomogeneity improved; however, the differences did
not reach significance (p = 0.053).
Limitations
The study represents a relatively small number of patients. This
was due to difficulties encountered with data collection, particu-
larly with relation to noisy signals obtained from the esophageal
monitoring and the EIT. Despite that we have selected mea-
surement techniques which do not interfere with the patients
breathing, the investigated infants were disturbed when the
esophagus probe was adjusted or the electrodes applied. Since
the use of HFNC is becoming more popular in many pediatric
hospitals, the understanding of the physiological mechanisms
is important. Not all changes that we observed were signifi-
cant, but they certainly were physiologically plausible. One fur-
ther limitation of the high-flow use is that the variation of the
applied positive airway pressure is greatly affected by air leaks
that occur around the nasal cannula and through the mouth.
Although EIT measurements in infants are technically
challenging with electrode placement difficulties increasing
recorded noise, the midthoracic placement of electrodes has
been confirmed by MRI to produce impedance values reflec-
tive of the entire lung (40).
How Can High Flow Be Defined?
Based on our findings, adequate flow rates are achieved when
increased positive expiratory Poe were observed and poten-
tially even positive airway pressures during the inspiratory
phase. The measurement of Poe for the titration of high flow
is clinically too cumbersome, similarly to the routine use of
EIT. Based on our and other recent studies, flow rates of greater
than 1.7 L/min/kg, probably for ease of use 2 L/kg/min, should
be discussed. These flow rates, however, should be tested in
larger studies and investigated whether any benefit can be
observed. We cannot yet provide any suggestions to the upper
limits of flow rates, but based on our own experience and a just
recently finished pilot study (41), flow rates of 2 L/kg/min for
infants with bronchiolitis are well tolerated. Artificial limita-
tions of the flow delivery systems have in the past limited the
investigation of higher flow rates.
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