Keywords
nasal high flow - continuous positive airway pressure - respiratory distress - neonate
Continuous positive airway pressure (CPAP) has become the mainstay for noninvasive
respiratory support in preterm neonates. Over the past decade, surveys of neonatal
networks have reported an increased use of nasal high flow (nHF) for noninvasive respiratory
support in preterm neonates.[1]
[2]
[3] The increased use of nHF has been attributed to its ease of application, lower incidence
of nasal injuries, and better patient and nursing comfort in comparison to nasal CPAP.[4]
[5]
[6]
[7] Recent studies have shown that nHF therapy resulted in higher rates of treatment
failure as compared with CPAP when used as the primary respiratory support mode in
preterm neonates >28 weeks of gestation.[8]
[9] However, 75% of the neonates in these studies were successfully managed with nHF.
Furthermore, the need for mechanical ventilation did not increase following primary
nHF therapy if CPAP was available as backup. Considering that nHF therapy could be
effective for primary respiratory support in a substantial proportion of preterm neonates,
it is essential to identify criteria and mechanisms that would facilitate applying
this intervention to select preterm populations in a manner that reduces treatment
failures.[10]
Increasing the nHF rates in neonates has shown to result in favorable physiological
effects such as generation of higher nasopharyngeal pressures, improved oxygenation,
enhanced CO2 elimination, and reduction in apneic episodes.[11]
[12]
[13] It is still unclear if these effects could translate into improved clinical outcomes
in preterm neonates. Recent studies have also reported large variability in the distending
pressures achieved with higher flow rates.[14]
[15] There are only few data available directly comparing different flow ranges in the
neonatal population. There is no consensus on optimal nasal flow rates for preterm
infants.[16] We conducted this randomized controlled trial to assess the effect of increased
(8–10 L/min) versus standard nasal flow (5–7 L/min) in reducing the need for higher
respiratory support and surfactant when applied as a primary respiratory support modality
for preterm neonates ≥28 weeks of gestation.
Materials and Methods
Trial Design and Settings
This single-center, parallel group, double-blinded randomized controlled trial was
conducted in the neonatal intensive care unit (NICU) of Surya Hospital, Mumbai between
October 15, 2017 and January 14, 2020. The study was approved by the institutional
ethics committee, and the trial was prospectively registered with the clinical trial
registry of India (CTRI/2017/10/010001). Written consent was obtained from one of
the parents prior to enrolment in the trial.
Participants
Moderately preterm (28–336/7 weeks) and late preterm infants (34–366/7 weeks) with respiratory distress (Silverman Andersen score ≥ 3) and/or FiO2 requirement ≥30% within the first 6 hours of birth were enrolled. Besides inborn
neonates, we also included eligible neonates born in maternity centers located within
a 3-km radius of our hospital. High-risk infant deliveries at these centers were conducted
only after arrival of our neonatal team. This facilitated early transfer of outborn
infants to our neonatal unit. Infants with birth weight <1,000 grams, hemodynamic
and/or neurological instability, air leak syndromes, prenatally diagnosed serious
congenital malformations, and those who received mechanical ventilation and/or surfactant
prior to NICU admission were excluded. Infants meeting the criteria for mechanical
ventilation at the time of study eligibility assessment were also excluded. Eligible
infants were transported by using mask CPAP or oxygen by nasal cannula.
Randomization
Eligible infants were randomized to either an initial nasal flow rate of 8 L/min (increased
nasal flow [INF]) or 5 L/min (standard nasal flow [SNF]). Randomization was stratified
for the gestational age (28–306/7, 31–336/7, and 34–366/7 weeks), and random sequences were generated in permuted variable blocks with sizes
2, 4, and 6. The sequence was generated by a statistician who was not involved in
the study enrolment process. Allocation concealment was done by using serially numbered,
opaque, and sealed envelopes.
Blinding
Upon enrolment in the study, the intensivist from the pediatric intensive care unit
was called to open the sealed envelopes and assign the infants to the allocated intervention.
The pediatric intensivist would set the initial flow and also conceal the flow rate
display by using paper strips ([Supplementary Fig. 1] [available in the online version]). Treating clinicians made subsequent flow rate
adjustments, as indicated. Thus, the treating clinicians, nurses, parents, and outcome
assessors were blinded to the initial flow rates and subsequent flow adjustments.
The starting flow rate was denoted as “F” liters/min in the medical charts and flow
increment or decrement by 1 L/min was recorded as “F ± 1” L/min along with the timing
of flow change. When the neonate was weaned off the nHF support or upgraded to CPAP/ventilator
support, the flow generator was switched off prior to discarding the paper strips.
This ensured blinding of the flow rates even after nHF support was ceased. Since the
flow rate display was concealed, it was important to ensure that the intended flow
rates were correctly dialed by the clinicians and that there were no discrepancies
between the prescribed and the set flow rate. Prior to the trial, all neonatal clinicians
anticipated to be involved in flow rate adjustments demonstrated competency in performing
blinded flow rate adjustments ([Video 1]). This run in period was also utilized to ensure that adequate clinical judgement
was demonstrated, and patient safety was not compromised through the blinding process.
Video 1 Setting up the airvo nasal high flow system and the blinding process.
Trial Protocol and Procedures
Enrolled infants were assessed every 15 to 30 minutes for the optimization of respiratory
support. FiO2 in both groups was titrated to maintain oxygen saturation between 92 and 95%. For
infants needing respiratory support escalation in either group, nasal flow rates were
increased to a predefined maximum level (7 L/min in SNF group and 10 L/min in INF
group) before considering CPAP support or surfactant administration. The sequence
of respiratory support and criteria for escalation and weaning of respiratory support
in this study are shown in [Fig. 1].
Fig. 1 Sequence of respiratory support escalation and weaning. INF, increased nasal flow;
INSURE, intubate–surfactant–extubate; SNF, standard nasal flow.
AIRVO 2 high-flow system (Fisher & Paykel healthcare, New Zealand) in the junior mode
(flow limits ranging from 2–25 L/min) was used to provide nasal flow therapy and Optiflow
Junior nasal cannula was used as the nasal interface. The interface was applied such
that the nasal prong diameter was less than 50% of the nostril of the neonate, thus
allowing egress of air as per manufacturer recommendations. The Fisher and Paykel
bubble CPAP system was used to provide rescue CPAP for the study infants. Caffeine
(10 mg/kg of base followed by a daily maintenance dose of 5–8 mg/kg/day) was administered
to all preterm neonates born before 32 weeks, starting on day 1 and continued until
34 weeks of postmenstrual age or discontinuation of respiratory support, whichever
was later.
Further details of trial protocol and procedures are provided in the [Supplementary Material] (available in the online version).
Outcomes and Sample Size
Our primary outcome was nHF failure within 120 hours of birth; a composite outcome
defined by the need for surfactant therapy or higher respiratory support (CPAP/mechanical
ventilation). Success with nHF was defined in those neonates that were exclusively
managed on nHF support from the time of randomization until 5 days of postnatal age.
Prespecified secondary outcomes were all-cause mortality, incidence of air leaks and
nasal injuries, and duration of respiratory support.
We have previously reported that 26% of preterm neonates on primary nHF therapy needed
higher respiratory support (CPAP/mechanical ventilation) within 72 hours of postnatal
age, and an additional 18% were rescued with surfactant by INSURE approach while on
nHF therapy.[17] Hence, in this study, we anticipated the baseline nHF failure rate to be 35%. Assuming
an absolute reduction in the failure rate from 35 to 17% by using high-nasal flow,
a sample of 100 patients in each group was required for a study power of 80% and two
tailed α error of 0.05.
The data and safety monitoring board reviewed the data after recruitment of 120 patients.
Interim analysis by an independent statistician blinded to the treatment allocation,
showed no clear evidence of harm or inferior efficacy in either group and recommended
that patient enrolment could continue.
Statistical Analysis
Descriptive statistics were used to summarize the data in both groups. Categorical
variables were compared with the Chi-square test, while continuous variables were
analyzed by using Student's t-test for normal distributions or the Wilcoxon rank-sum test for skewed distributions.
Relative risk and median differences (Hodges–Lehmann estimates) were computed along
with 95% confidence intervals. Analysis was done by intention to treat principle.
No adjustments were done for multiple comparisons.
Considering the potential impact of nasal flow rate increments on nHF success- failure
rates, we performed post hoc sensitivity analysis to compare flow rate increments
in our study groups. Kaplan–Meier curves were plotted to compare the rates of nHF
success and flow increments in both groups. We constructed violin plots to depict
the distributional ranges and densities of nasal flow rates in the first 48 hours
in both groups. We also conducted ancillary analyses to investigate the association
of nHF failure with patient characteristics at study entry. A two tailed p-value of <0.05 was considered to be statistically significant. Stata Version 13.1
(Statacorp, 4905 Lakeway Drive, College station, TX) was used for all the analyses
and graphical displays.
Results
A total of 212 neonates were enrolled in the study. In all, 128 neonates (60%) were
between 31 and 34 weeks of gestation, 52 (25%) were <31 weeks, and 32 (15%) were >34
weeks. The primary outcome was analyzed in 209 infants. The details of the study enrolment
process are shown in [Fig. 2]. The final diagnosis was respiratory distress syndrome in all except five infants
in the late preterm subgroup (two in the SNF group and three in the INF group); these
infants were diagnosed to have transient tachypnea of newborn. The maternal and infant
baseline characteristics were similar in both groups ([Table 1]).
Fig. 2 Flow diagram of patient enrolment process. *High-flow system had to be reset or replaced
due to malfunction during the study period resulting in unblinding of the flow rates.
Table 1
Baseline characteristics
|
Baseline characteristics
|
Standard nasal flow (n = 108)
|
High-nasal flow (n = 104)
|
p-Value
|
|
Maternal characteristics
|
|
Maternal age (y)
|
33 (30–36)
|
32 (29–36)
|
0.27
|
|
Multiple pregnancy
|
49 (45%)
|
40 (38%)
|
0.31
|
|
Pregnancy-induced hypertension
|
35 (32%)
|
28 (27%)
|
0.38
|
|
Antepartum hemorrhage
|
12 (11%)
|
6 (5.8%)
|
0.16
|
|
Gestational diabetes
|
19 (18%)
|
25 (24%)
|
0.25
|
|
PPROM > 24 h
|
16 (15%)
|
21 (20%)
|
0.30
|
|
Cesarean delivery
|
99 (92%)
|
97 (93%)
|
0.83
|
|
Any prenatal steroid exposure
|
107 (99%)
|
99 (95%)
|
0.5
|
|
Complete course of prenatal steroids
|
87 (81%)
|
75 (72%)
|
0.15
|
|
Infant characteristics
|
|
Gestational age (wk)
|
32.4 ± 1.6
|
32.4 ± 1.9
|
0.73
|
|
Gestation (wk)
|
|
|
|
|
28–306/7
|
24 (22%)
|
28 (27%)
|
|
|
31–336/7
|
67 (62%)
|
61 (59%)
|
|
|
34–366/7
|
17 (16%)
|
15 (14%)
|
|
|
Birth weight (g)
|
1,634 ± 415
|
1,657 ± 470
|
0.71
|
|
Outborn
|
49 (45%)
|
48 (46%)
|
0.9
|
|
Male sex
|
64 (59%)
|
58 (56%)
|
0.6
|
|
Small for gestational age
|
15 (14%)
|
14 (13%)
|
0.7
|
|
Need for positive pressure ventilation at birth
|
24 (22%)
|
34 (33%)
|
0.9
|
|
Apgar's score at 5 min
|
7 (7–8)
|
7 (7–8)
|
0.18
|
|
SNAPPE score
|
5 (5–11)
|
5 (5–9)
|
0.83
|
|
Capillary or arterial pH before randomization
|
7.25 ± 0.06
|
7.25 ± 0.05
|
0.83
|
|
PaCO2 before randomization (mm Hg)
|
54.3 ± 10
|
54.3 ± 9.5
|
0.98
|
|
Baseline FiO2 at randomization
|
0.35 (0.3–0.4)
|
0.35 (0.3–0.4)
|
0.95
|
|
Time of admission (min)
|
20 (15–60)
|
22 (15–60)
|
0.3
|
|
Time of initiation of nHF (min)
|
30 (15–60)
|
30 (15–60)
|
0.86
|
|
CPAP prior to randomization
|
47 (44%)
|
42 (40%)
|
0.66
|
|
Prerandomization CPAP duration (min)
|
30 (15–45)
|
30 (15–50)
|
0.80
|
Abbreviations: PPROM, preterm premature rupture of membranes; SA Silverman Andersen
score; SNAPPE II, Score for Neonatal Acute Physiology-Perinatal Extension II.
Note: Data expressed as n (%), mean ± standard deviation or median (25th–75th percentile).
The nHF failure rate was 22% (n = 22) in the INF group and 29% (n = 31) in the SNF group (p = 0.22; p = 0.26 by log rank test, [Supplementary Fig. 2] [available in the online version]). The need for mechanical ventilation was not
significantly different between the groups. (3.7 vs. 3.9%, p = 0.94). Of the two deaths, one occurred at 48 hours of age due to refractory pulmonary
hypertension. The other infant developed necrotizing enterocolitis stage III on day
30 of postnatal age and expired four days later. None of the infants in the increased
flow group developed pneumothorax. Other neonatal morbidities were similar in both
the study groups ([Table 2]).
Table 2
Neonatal outcomes
|
Outcomes
|
Standard nasal flow group (n = 107)
|
Increased nasal flow group (n = 102)
|
Relative risk/median difference (95% CI)
|
p-Value
|
|
Treatment failure
|
|
nHF Failure[a]
|
31 (29%)
|
22 (22%)
|
0.81 (0.57–1.15)
|
0.22
|
|
28–306/7 wk
|
12/23 (52%)
|
11/26 (42%)
|
0.83 (0.48–1.42)
|
0.34
|
|
31–336/7 wk
|
14/67 (21%)
|
11/61 (18%)
|
0.91 (0.56–1.48)
|
0.71
|
|
34–366/7 wk
|
5/17 (29%)
|
0/15
|
0
|
0.03
|
|
CPAP
|
24 (22%)
|
21 (20%)
|
0.94 (0.67–1.34)
|
0.75
|
|
CPAP days (in nHF failure)
|
9 (6–15)
|
8 (5–17)
|
−1 (−4 to 4)
|
0.63
|
|
Surfactant
|
29 (27%)
|
18 (18%)
|
0.74 (0.50–1.09)
|
0.10
|
|
Mechanical ventilation
|
4 (3.7%)
|
4 (3.9%)
|
1.02 (0.50–2.08)
|
0.94
|
|
Reasons for nHF failure
|
|
Increased oxygen need and respiratory distress
|
16 (52%)
|
11 (50%)
|
0.96 (0.51–1.82)
|
1.00
|
|
Apnea and respiratory acidosis
|
2 (6.4%)
|
2 (9%)
|
1.22 (0.43–3.45)
|
1.00
|
|
Increased oxygen need and respiratory acidosis
|
2 (6.4%)
|
2 (9%)
|
1.22 (0.43–3.45)
|
1.00
|
|
Increased respiratory distress and decreased lung expansion on chest radiograph
|
4 (13%)
|
3 (14%)
|
1.04 (0.41–2.6)
|
1.00
|
|
Increased oxygen need
|
5 (16%)
|
2 (9%)
|
0.65 (0.19–2.2)
|
0.68
|
|
Increased respiratory distress
|
2 (6.4%)
|
2 (9%)
|
1.22 (0.43–3.45)
|
1.00
|
|
Time to nHF failure (hours)
|
3 (1.5–4.5)
|
3 (2–4.5)
|
−0.25 (−1 to 1)
|
0.72
|
|
Duration of primary nHF therapy
|
5 (2–7)
|
4 (2–7)
|
0 (−1 to 1)
|
0.71
|
|
Restarting of respiratory support after week 1
|
4 (3.7%)
|
5 (4.8%)
|
1.14 (0.63–2.09)
|
0.70
|
|
Nasal flow rates
|
|
Median nasal flow rate (L/min)
|
6 (5–7)
|
7 (7–8)
|
2 (1–3)
|
0.008
|
|
Maximum nasal flow rate (L/min)
|
7 (5–7)
|
8 (8–10)
|
3 (3–3)
|
0.001
|
|
Nasal flow rate increments (%)
|
68 (64%)
|
44 (43%)
|
0.66 (0.49–0.87)
|
0.004
|
|
Proportion of infants at specified flow rates
|
|
(“F” L/min)[b]
|
39 (36%)
|
58 (57%)
|
|
|
|
(“F + 1” L/min)
|
15 (14%)
|
13 (13%)
|
|
|
|
(“F + 2” L/min)
|
53 (49%)
|
31 (30%)
|
|
|
|
Reasons for flow increments
|
|
Increased respiratory distress
|
25/68 (37%)
|
19/44 (43%)
|
1.17 (0.74–1.86)
|
0.47
|
|
Increased oxygen need
|
18/68 (26%)
|
11/44 (25%)
|
0.95 (0.56–1.63)
|
0.84
|
|
Decreased lung expansion
|
12/68 (17%)
|
6/44 (14%)
|
0.82 (0.41–1.65)
|
0.56
|
|
Respiratory acidosis
|
6/68 (8.8%)
|
4/44 (9%)
|
1.02 (0.46–2.26)
|
0.97
|
|
Apnea or other causes
|
7/68 (10%)
|
4/44 (9%)
|
0.92 (0.40–2.08)
|
0.82
|
|
Nasal flow increments in nHF success
|
49% (37/76)
|
27% (22/80)
|
0.62 (0.43–0.88)
|
0.008
|
|
Proportion of infants at specified flow rates
|
|
(“F” L/min)[b]
|
39 (51%)
|
58 (73%)
|
|
|
|
(“F + 1” L/min)
|
15 (20%)
|
12 (15%)
|
|
|
|
(“F + 2” L/min)
|
22 (29%)
|
10 (12%)
|
|
|
|
Caffeine
|
95 (89%)
|
87 (86%)
|
0.86 (0.59–1.24)
|
0.45
|
|
Days on caffeine
|
14 (8–21)
|
12 (7–20)
|
−1 (−2 to 4)
|
0.58
|
|
Duration of respiratory support (overall cohort) (d)
|
6 (4–9)
|
5 (4–8)
|
0 (−1 to 1)
|
0.36
|
|
Bronchopulmonary dysplasia
|
4 (3.7%)
|
4 (3.9%)
|
1.02 (0.50–2.08)
|
0.94
|
|
Other outcomes
|
|
All-cause mortality
|
1 (0.9%)
|
1 (0.9%)
|
1.02 (0.25–4.12)
|
0.97
|
|
Intraventricular hemorrhage (grade III or higher)
|
1 (0.9%)
|
1 (0.9%)
|
1.04 (0.06–16.4)
|
0.97
|
|
Air leak syndromes
|
1 (0.9%)
|
0
|
|
1.00
|
|
Culture positive sepsis
|
7 (6.5%)
|
6 (5.9%)
|
0.94 (0.51–1.72)
|
0.94
|
|
Patent ductus arteriosus (needing medical treatment)
|
8 (7.5%)
|
4 (3.9%)
|
0.67 (0.30–1.51)
|
0.26
|
|
Necrotizing enterocolitis (stage 2 or higher)
|
3 (2.8%)
|
3 (2.9%)
|
1.02 (0.45–2.31)
|
0.95
|
|
Retinopathy of prematurity (requiring treatment)
|
5 (4.7%)
|
3 (2.9%)
|
0.62 (0.15–2.54)
|
0.51
|
|
Time to reach full feeds (d)
|
4 (2–6)
|
4 (2–6)
|
0 (−1 to 0)
|
0.48
|
|
Time to full oral feeds (d)
|
15 (7–21)
|
12 (6–24)
|
0 (−3 to 3)
|
0.91
|
|
Duration of hospital stay (d)
|
23 (12–32)
|
22 (10–36)
|
1 (−1 to 2)
|
0.78
|
|
Nasal injury
|
9 (8.4%)
|
6 (5.9%)
|
0.80 (0.43–1.53)
|
0.80
|
Abbreviations: CI, confidence interval; CPAP, continuous positive airway pressure;
nHF, nasal high flow.
Note: Data expressed as n (%), (n/N) % or median (25th–75th percentile). The p-values are based on Chi-square test and two sample t-test/Wilcoxon rank sum test for categorical and continuous variables.
a nHF failure defined as need for CPAP or mechanical ventilation or surfactant.
b “F” liters/min denotes the starting flow rate in each group (5 L/min in the standard
group and 7 L/min in the increased flow group).
c Dilation of nares, columella indentation or excoriation, notching on the bridge of
the nose, redness/bleeding/excoriation of any area of nose.
We observed a bimodal distribution of the flow rates in the SNF group ([Fig. 3]) suggesting that flow rate increments were more frequent in the group initiated
on nHF rate of 5 L/min. (64 vs. 43%, p = 0.003, p = 0.006 by log-rank test, [Supplementary Fig. 2] [available in the online version]). The median maximal nasal flow rates were 7 L/min
in the SNF group and 8 L/min in the INF group. Only 36% of patients (n = 39) in the SNF group were successfully supported with flow rates of 5 L/min. The
flow rates were either 7 or 8 L/min in more than half of the study infants (53%).
Flow rates greater than 8 L/min were required in 21% infants (n = 44). Among infants that were exclusively managed on nHF support (nHF success, n = 156), nasal flow rates had to be increased in 49% (n/N = 37/76) of the patients
in the SNF group as compared with 27% (n/N = 22/80) in the INF group (p = 0.008).
Fig. 3 Nasal flow rate distribution plots. Violin plots showing nasal flow rate distribution
at 3 hourly time intervals in the first 48 hours of life in the standard nasal flow
group (light shaded violins) and increased nasal flow group (dark-shaded violins).Two
flow peaks (at 5 and 7 L/min) noted in the standard flow group at every time point,
indicating the increased frequency of flow escalation in that group.
Infants that failed nHF had significantly lower gestational age, higher baseline SA
scores and oxygen requirements. The overall duration of respiratory support was also
significantly longer in the nHF failure cohort. ([Supplementary Table 1] [available in the online version])
Discussion
Our study shows that higher nasal flow rate (8–10 L/min) did not reduce the combined
need for higher respiratory support or surfactant therapy among preterm infants ≥28
weeks of gestation with respiratory distress since birth. However, the frequency of
nasal flow rate escalation was significantly higher in the group initiated on flow
rates of 5 L/min, suggesting that starting flow rates of 5 L/min may not be optimal
for preterm neonates on primary nasal flow support. Most of the study infants that
were stabilized with nasal flow support required flow rates of 7 to 8 L/min.
Recent studies have demonstrated that increasing nasal flows could significantly increase
nasopharyngeal and oesophageal PEEP, potentially simulating a CPAP effect.[18]
[19] In our RCT, the overall nHF failure rate remained the same in both groups. Our findings
add to the existing evidence that suggests 20 to 25% failure rates with primary nHF
therapy in preterm neonates. The rate of mechanical ventilation in our study cohort
(<5%) was lower than that reported in recent studies involving primary nHF therapy.[8]
[20] While the mean gestational ages were similar across the studies, the use of INSURE
and rescue CPAP could have contributed to a lower rate of mechanical ventilation in
our study.
The current trial was pragmatic in allowing flow rate increments in both groups before
switching over to higher respiratory support. As a result, although nHF failure occurred
only in a quarter of the patients, an escalation in the flow rate was required in
approximately 54% (n = 114) of our study patients. A significantly higher proportion of infants in the
SNF group needed early increments in flow rate to avert treatment failure. The fact
that a flow rate of less than 6 L/min was optimal only for 36% of the infants in the
SNF group also suggests the need for optimized flow settings in neonates. At least
one prior study has found that a nasal flow rate of 3 to 5 L/min was similarly efficacious
to CPAP in preterm infants >28 weeks of gestation[21]; therefore, the effectiveness of lower flow rates (5 L/min) in certain preterm infants
cannot be ruled out.
We also found that approximately 50% of the infants with gestational age <31 weeks,
failed nHF and were stabilized with higher respiratory support, highlighting the need
for cautious use of nasal flow therapy. Observed associations of nHF failure with
higher levels of oxygen and lower gestational age in our study, similar to previous
reports,[22]
[23] provide additional clinical insights to identify a selected population for application
of nHF. Preterm infants with gestational age of 34 to 366/7 weeks and those with a prerandomization FiO2 of ≤30% could be considered ideal candidates for primary nHF application.
A major strength of the study was the blinding of flow rates, ruling out performance
bias in the interpretation of the primary outcome and the flow increments. High-prenatal
steroid exposure rates make this cohort generalizable to populations with similar
access to high quality maternal and neonatal care.
Our study had certain limitations. Intentionally, the effect of INF rates was not
compared with CPAP, the current standard of noninvasive respiratory support in preterm
neonates. Rather, we aimed to study the clinical effects of different nasal flow ranges
that could have important implications for centers that continue to employ nHF for
primary respiratory support in preterm neonates. Although the starting flow rates
in both groups were distinctly different, the difference in the maximally achieved
flow rates between the groups was small and could have led to similar failure rates
in the two groups. Our findings are not generalizable to extremely preterm neonates
or those with severe respiratory distress that requires mechanical ventilation at
the outset. Some of the criteria used for escalation of flow rates, such as respiratory
distress and lung expansion, were subjective. Although blinding reduces the risk of
bias, the subjective element in the primary outcome is another limitation. Prerandomization
CPAP use (in the delivery room and briefly during transport) in this study could also
have impacted the primary outcome.
A proportion of infants (21%) in our study were exposed to nasal flow rates greater
than 8 L/min that are not licensed for use in neonates outside of research settings.
Although there were no air leaks noted in the higher flow group in this study, the
safety of higher nasal flows (>8 L/min) in neonates remains an important issue. A
recent multicenter study comparing higher nasal flow therapy (3 L/kg/min) versus standard
flows (2 L/kg/min) in older infants with bronchiolitis reported greater discomfort
and prolonged ICU length of stay in the high flow group.[24] Flow rates greater than 8 L/min are currently not approved in premature infants.
The nasal injury reported in the study occurred in the infants that failed nHF, typically
in the 28 to 31 weeks of subgroup and were CPAP related.
In summary, higher initial nasal flows, despite being safe, did not reduce the need
for higher respiratory support among moderately preterm neonates presenting with respiratory
distress since birth. Nasal flow rates of 5 L/min were not optimal for most preterm
infants receiving primary nasal flow therapy. Careful patient selection and optimization
of flow settings are important considerations in the use of primary nasal flow therapy
in preterm neonates.
