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Journal of Critical Care 35 (2016) 138144

Contents lists available at ScienceDirect

Journal of Critical Care


journalhomepage:www.jccjournal.org

Comparison of high-flow nasal oxygen therapy with conventional oxygen


therapy and noninvasive ventilation in adult patients with acute
hypoxemic respiratory failure: A meta-analysis and systematic
,,
review
a b, b
Souvik Maitra, MD, DNB , Anirban Som, MD , Sulagna Bhattacharjee, MD, DNB ,
b b
Mahesh K. Arora, MD , Dalim K. Baidya, MD
a Department of Anaesthesia & Intensive Care, PGIMER, Chandigarh, 160012, India
b Department of Anaesthesiology, Pain Medicine & Critical Care, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
article info abstract

Keywords: Purpose: The role of high-flow nasal oxygen (HFNO) therapy in adult patients with acute hypoxemic respiratory failure is
High-flow nasal oxygen controversial.
NIV Methods: This meta-analysis of prospective randomized controlled trials (RCTs) has been designed to compare HFNO with
CPAP noninvasive ventilation (NIV) and conventional oxygen therapy in such patients.
Acute respiratory failure
Results: Initial database searching revealed 336 RCTs, of which 7 were included in this meta-analysis. Five RCTs compared
High flow oxygen
HFNO with standard oxygen therapy, one compared HFNO with NIV, and one compared all three. HFNO did not decrease the
requirement of higher respiratory support compared with control group. HFNO was associated with improved respiratory rate
and dyspnea score, and better comfort in 3 RCTs, whereas other studies did not find any difference.

Conclusion: High-flow nasal oxygen does not offer any benefit over NIV or conventional oxygen therapy in terms of
requirement of higher respiratory support.
2016 Elsevier Inc. All rights reserved.
e d
d d
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s
High-flow oxygen therapy that use of HFNO in the emergency
s
through a nasal cannula is a department (ED) is associated with
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technique whereby heated and F
a less requirement of higher
i
humidified oxygen is delivered to n respiratory support in patients with
n
the nose at high flow rates [1]. High a i acute re-spiratory failure (ARF).
flow rates of oxygen generate a n r HFNO has also been found to
c b
positive pres-sure in the upper improve thoracoabdominal
i a
airway [2] and also decrease n synchrony in such patients [8].
a
physiological dead space by l s This meta-analysis has been
washing out carbon dioxide. High- m designed to determine the
flow nasal oxygen (HFNO) therapy d @ effectiveness of HFNO in
i g
is increasingly being used in adult s comparison to NIV and face mask
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patients with acute hypox-emic c oxygen for acute hypoxemic
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widespread use in pediatric patients, o
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adults is lacking [3,4]. A number of c
r 1. Methods
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well-designed randomized
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controlled trials have compared This meta-analysis follows the
HFNO with non-invasive ventilation n Preferred Reporting Items for
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(NIV) and conventional face mask o Systematic Reviews and Meta-
n A
oxygenation. Frat et al [1] in a large . Analyses (PRISMA) statements [9].
e
well-designed trial found that use of . S A protocol of this meta-analysis has
NIV, standard ox-ygen therapy, and Acknowledgment: none. o not been registered.
HFNO is associated with similar C m
intubation rates. Schwabbauer et al o )
r .
[5] found that HFNO offers a good 1.1. Eligibility criteria
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balance between oxygenation and e http
patients' comfort. However, HFNO s ://d Prospective randomized
was not shown to reduce the need p x.d
for mechanical ventilation in such o oi.o controlled trials where
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HFNO therapy has been
oxygen therapy [6]. On the contrary,
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S. Maitra et al. / Journal of Critical Care 35 (2016) 138144 139

Fig. 1. PRISMA flow diagram.


1.2. Information sources 1.6. Data items

PubMed and Cochrane Central The following data were


Register of Controlled Trials were collected and tabulated in an Excel
searched electronically from data sheet: first author of the study,
inception until February 19, 2016, year of publication, geographical
for po-tentially eligible trials. loca-tion of the study, patient
References of the related trials were population and inclusion criteria,
also manually searched. study setting, duration of therapy
under study, rate of escalation of
1.3. Search strategy respiratory sup-port, improvement in
respiratory rate, dyspnea score,
PubMed was searched with the comfort score, length of stay in the
following search words: high flow ED, and mortality.
nasal cannula, high flow nasal
oxygen, high flow nasal oxygen 1.7. Risk of bias in individual studies
therapy, acute respiratory failure, and
respiratory failure. Duplicate The quality of eligible trials was
publica-tions were identified assessed using the risk of bias tool
electronically in EndNote software within Review Manager, version
(Endnote X5; Thomson Reuters, 5.2.3 software (Review Manager
Philadelphia, PA). No language [RevMan] version 5.2, Copenhagen:
restriction was imposed. For The Nordic Cochrane Centre, The
identification of the ongoing or Cochrane Collaboration, 2012) by 2
unpublished trials, International authors working independently (SM
Clinical Trials Registry Platform was and SB). Random sequence
searched with the same search generation, allocation concealment,
words. blinding, incomplete data, and
selective reporting were assessed;
based on the method of the trials,
1.4. Study selection each was graded yes, no, or un-
clear, which reflected a high risk of
Prospective randomized bias, low risk of bias, and uncertain
controlled trials where HFNO bias, respectively.
therapy was compared with either
conventional oxygen therapy or NIV
or both in adult patients with acute 1.8. Summary measures and
hypoxemic respiratory failure have synthesis of results
been in-cluded in this meta-analysis.
Primary outcome measure of this
1.5. Data collection process meta-analysis was the require-ment
of higher respiratory support.
Two authors (SM and AS) Secondary outcomes were respira-
independently extracted all the tory rate, dyspnea score, and comfort
relevant data from the full text of the score.
trials. We did not ask the authors Statistical analyses were done in
Review Manager, version 5.2.3 soft-
about unpublished data. Tabulated
ware (Review Manager [RevMan]
data were rechecked by another
Version 5.2, Copenhagen: The
author (DKB).
Nordic Cochrane Centre, The
Cochrane Collaboration, 2012).
If the values were reported as
median and an interquartile range or
total range of values, the median
itself was used to estimate mean for
Table 1
Characteristics of individual studies

Study Country Setting Diagnosis/cause of ARF Control Duration of therapy Primary outcome Secondary outcome
Bell et al, 2015 Australia ED COPD, asthma, respiratory Standard oxygen therapy 2h Reduction in respiratory Self-reported dyspnea score,
tract infection, pulmonary (nasal prongs or face mask: rate by 20% or escalation comfort score (at 1 h), disposition
embolism, cancer. Venturi/nonrebreather) in ventilation within 2 h from ED (admission to ward, ICU,

S. Maitra et al. / Journal of Critical Care 35 (2016) 138144


Cardiac cause or discharge), length of stay in ED
Frat et al, 2015 France ICU Pneumonia, extrapulmonary Standard oxygen therapy 2d Proportion of patients Mortality in ICU, 90-d mortality,
sepsis, aspiration, other (nonrebreather face mask) requiring intubation no. of ventilator-free days,
and noninvasive ventilation within 28 d length of ICU stay, dyspnea and
comfort scores, complications
Jones et al, 2016 New Zealand ED COPD, pneumonia, heart Standard oxygen therapy 3h Conversion to noninvasive Length of stay in ED and hospital,
failure, asthma, mixed, (Hudson mask, Venturi or invasive 90-d mortality, adverse effects,
other device, or standard ventilation comfort score, ICU admission rate,
nasal prongs) in-hospital mortality, mechanical
ventilation within 24 h of admission
Lemiale et al, 2015 France ICU (immunocompromised Sepsis, cardiogenic pulmonary Standard oxygen therapy 2h Conversion to noninvasive VAS scores for comfort, thirst and
patients) edema, noninfectious pulmonary (Venturi mask) or invasive ventilation dyspnea, respiratory rate, and
disease, lung involvement by within or at 2 h heart rate
underlying malignancy,
pleural effusion, pneumonia,
miscellaneous
Parke et al, 2011 New Zealand CTVS ICU Vascular, cardiac, and thoracic Standard oxygen therapy 24 h Rate of noninvasive PaO2/FIO2, length of ICU stay
(postoperative surgery, cardiologic and respiratory (Hudson face mask) ventilation
patients)
Rittayamai et al, 2015 Thailand ED Heart failure, COPD, Standard oxygen therapy 1h Dyspnea score Respiratory rate, heart rate,
asthma, pneumonia, other (nasal prongs or blood pressure, subject
nonrebreather mask) comfort, adverse events,
hospitalization rate
Stephan et al, 2015 France CTVS ICU Cardiac, thoracic, and vascular BiPAP Period of Treatment failure Respiratory variables, dyspnea
(postoperative surgery, heart and/or lung ICU stay (reintubation for score, comfort score, skin breakdown
patients) transplantations mechanical ventilation, score, respiratory and extrapulmonary
switch to the other study complications, and number of
treatment, or premature bronchoscopies. Post hoc exploratory
study treatment outcomes included number of
discontinuation) nurse interventions for unplanned
device displacement and mortality,
length of ICU stay

BiPAP- bilevel positive airway pressure, COPD- chronic obstructive pulmonary disease, CTVS- cardiothoracic and vascular surgery, FiO 2- fraction of inspired oxygen, PaO2- partial pressure of oxygen (arterial), VAS- visual analogue
scale.
140
S. Maitra et al. / Journal of Critical Care 35 (2016) 138144 141
calculated with 95% confidence interval (95% CI). The Q test was used to
2
analyze heterogeneity of trials. When I was greater than 50%, it was
considered as heterogeneous, and the M-H or inverse variance ran-dom
effects model was used; otherwise, the fixed effects model was used. The
number needed to treat was calculated from the odds ratio (OR) in Visual Rx
online software (Visual Rx version 3.0, Dr Chris Cates,
http://www.nntonline.net/visualrx/). Where a pooled analysis was not
possible, we performed a qualitative synthesis of the reported data.

Publication bias was tested by visual inspection of funnel plot and Egger
regression test in Comprehensive Meta-analysis soft-ware (Comprehensive
Meta-Analysis, version 2.2.034, 2006; Biostat, Englewood, NJ).

2. Results

Initial database searching revealed 336 articles, which were screened from
title and abstract to identify potentially eligible trials. Full texts of 10 articles
were assessed, and finally 7 randomized con-trolled trials (RCTs) [1,6,7,11
14] were included in this meta-analysis. A PRISMA flow diagram showing
selection of studies has been shown in Fig. 1. The characteristics of individual
studies have been presented in Table 1. In 3 RCTs [6,7,11], the study setting
was the ED; and in 2 stud-ies each, it was the ICU [1,12] and cardiothoracic
postoperative ICU [13,14]. Five studies [6,7,1113] compared HFNO with
standard oxygen therapy, which included nasal prongs and/or face masks. One
study [14] compared BiPAP (bilevel positive airway pressure) with HFNO,
whereas another RCT [1] compared HFNO vs standard oxygen therapy vs
NIV. The risks of bias summary in individual studies has been shown in Fig.
2. Blinding of patients and personnel was not possible in any RCT be-cause of
practical reasons. Visual inspection of funnel plot (Fig. 3) and Egger
regression test (P = .479) did not reveal any publication bias.

2.1. Requirement of higher respiratory support

Pooled analysis from 5 studies [1,6,7,12,13] shows that there is a trend of


Fig. 2. Risk of bias summary. HFNO decreasing the requirement of higher respiratory support compared
with standard oxygen therapy, although it did not reach the level of statistical
2
significance (OR, 0.50; 95% CI, 0.23-1.07; M-H ran-dom; n = 759; I = 60%)
(Fig. 4). Also, results from 2 studies [1,14] show no difference in this
outcome between HFNO- and NIV-treated patients (OR, 0.80; 95% CI, 0.52-
samples greater than 25. The standard deviation was estimated from the 2
median and the low and high end of the range for samples smaller than 15, as 1.23; M-H random; n = 1046; I = 48%) (Fig. 5).
range/4 for samples from 15 to 70, and as range/6 for sam-ples more than 70.
If only an interquartile range was available, standard deviation was estimated
as interquartile range/1.35 [10]. 2.2. Respiratory rate
We calculated the following: (1) the risk ratio (RR) for each di-chotomous
outcome at individual study level, (2) the pooled RR using the Mantel- Three studies reported a statistically significant decrease in respira-tory
Haenszel (M-H) method, (3) mean difference for each con-tinuous outcome at rate in the patients managed with HFNO compared with those in the control
individual study level, and (4) pooled mean differ-ence using inverse variance group [1,7,14]. On the contrary, 3 other studies failed to show any difference
method. All statistical variables were [6,11,12]. No statistically significant difference
Funnel Plot of Standard Error by Log odds ratio
0.0
0.2

0.4

Error
0.6

Standard
0.8
1.0

-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0

Log odds ratio


Fig. 3. Funnel plot for publication bias.
142 S. Maitra et al. / Journal of Critical Care 35 (2016) 138144

Fig. 4. Requirement of higher respiratory support: HFNO vs standard oxygen therapy.

Fig. 5. Requirement of higher respiratory support: HFNO vs NIV.


was found on pooled analysis of respiratory rate at 1 hour (MD [mean in the HFNO group (85.9% vs 74.2%; P = .08). The other 2 studies did not
difference], 1.5; 95% CI, 3.58 to 0.59; Inverse-variance random; n = 440; P find any difference in the comfort level of the intervention and con-trol groups
2 [12,14] (Table 4).
= .16; I = 56%) (Table 2, Fig. 6).

2.3. Dyspnea score


2.5. Length of stay in ED
Bell et al [7] found that 75% from the HFNO group reported decrease in
Borg score at the end of 2 hours compared with 55.8% from the con-trol In 2 studies [6,7] that reported this outcome, length of stay in the ED was
group (P = .044). Frat et al [1] reported statistically significant im-provement similar in both HFNO and control groups (Table 5).
in dyspnea scores (P b .01) as well as in proportion of patients with improved
dyspnea (P b .001) at 1 hour in the HFNO group in comparison to both
standard oxygen and NIV groups. The study by Rittayamai et al [11] 2.6. Mortality
corroborates this finding (P = .01). On the other hand, the other 3 studies
reporting this parameter did not find any difference between the groups Only 2 studies reported data regarding mortality [1,6]. Frat et al [1]
[6,12,14] (Table 3). reported lower mortality (both in ICU and at 90 days) in the HFNO group
compared with the standard oxygen therapy and NIV groups. On the other
2.4. Comfort score hand, Jones et al [6] did not find any difference in in-hospital and 90-day
mortality between HFNO and control groups. Pooled analysis of 90-day
In concordance with improvement in dyspnea score, 3 studies [1,7,11] mortality did not show any difference be-tween HFNO and standard oxygen
found that the patients in the HFNO group were more comfort-able than those therapy (OR, 0.91; 95% CI, 0.43-1.93; n = 503; P = .8; M-H random). ICU
in the control group with statistical significance. In the study by Jones et al [6], mortality did not differ be-tween HFNO and NIV in pooled analysis (OR,
a higher proportion of patients in the standard oxygen therapy group felt more 0.70; 95% CI, 0.22-2.26; n = 1046; P = .55; M-H random).
comfortable than their counterparts
Table 2
Respiratory rate (RR) (mean [SD])

Study name Parameter Time point HFNO Standard oxygen therapy NIV P
Bell et al % of patients with 2h 66.7% (n = 48) 38.5% (n = 52) .005
N20% decrease in RR
Frat et al RR 1h 28 (7) 31 (7) 31 (8) b.01
(n = 106) (n = 94) (n = 110)
Jones et al RR 1h 26.7 (n = 115) 26.6 (n = 85) .92
Rittayamai et al RR 1h 26 (6.2) 27.5 (4.9) .82
(n = 20) (n = 20)
Lemiale et al RR 2h 25 (22-29) 25 (21-31) Not mentioned
(n = 52) (n = 48)
Stephan et al RR 1h 21 (20.4-21.7) 23 (22.3-23.7) b.001
(n = 414) (n = 416)
S. Maitra et al. / Journal of Critical Care 35 (2016) 138144 143

Fig. 6. Respiratory rate at 1 hour: HFNO vs standard oxygen therapy.


3. Discussion shares the advantages of HFNO like titrating flow and FIO2 separately and
providing positive end-expiratory pressure, with the distinct disad-vantage of
The most important finding of this meta-analysis is that HFNO does not poor patient comfort and compliance [19].
offer any benefit over NIV or conventional oxygen therapy in terms of Reductions in respiratory rate, dyspnea score, and comfort score are all
requirement of higher respiratory support. interlinked. Some RCTs have reported HFNO to be better in these pa-
The most important advantage of HFNO is the ability to titrate both flow rameters, whereas others did not find any difference with the control group.
and fraction of inspired oxygen (FIO2) separately [7]. This ability to titrate So, HFNO is at least as comfortable as standard oxygen therapy or NIV. This
FIO2 may be beneficial to patients who are prone to develop hy-percapnia [15]. can be explained by the following mechanisms: reduced an-atomical dead
space [15,20], a low level of positive end-expiratory pres-sure [21], improved
FIO2 may be adjusted from 0.21 to 1.0, as it allows mini-mal room air
thoracoabdominal synchrony [8], and decreased symptoms of mucosal
entrainment [7]. Flow, on the other hand, is set equal to or greater than the
patient's inspiratory flow demand and titrated to the work of breathing [16]. dryness [22,23].
With respect to length of stay in ED and mortality, no study was ad-
But the role of HFNO in ARF is an open question, and the recent re-views equately powered or designed to assess these outcomes meaningfully.
[15,17] of HFNO have not dealt with this in detail. The RCTs have included patients with ARF from various etiologies,
Although the results of RCTs have been inconsistent regarding esca-lation namely, pneumonia, extrapulmonary sepsis, chronic obstructive pul-monary
of respiratory support, this meta-analysis shows that there is a trend toward disease (COPD), asthma, heart failure, and post cardiothoracic surgery.
improved outcomes with HFNO compared with standard oxygen therapy, Different subsets of patients in this heterogeneous population are unlikely to
which is not statistically significant. This potential ben-efit has been attributed benefit equally from a particular initial respiratory sup-port. Severity of ARF
to enhanced mucociliary clearance and in-creased patient tolerance. [13,18]. at presentation should also be taken into account, with a lower partial pressure
of oxygen (arterial)/FIO2 and higher respi-ratory rate and Simplified Acute
High-flow nasal oxygen has been compared with NIV in only 2 RCTs Physiology Score II shown to be associ-ated with HFNO failure [24]. All
[1,14]; and pooled analysis does not show any difference in requirement of these explain the contradicting results of the RCTs and the inconclusive result
higher respiratory support. This finding reflects the fact that NIV of this meta-analysis.

Table 3
Dyspnea score (mean [SD] or median [IQR]) or proportion of patients with improvement in dyspnea score (%)

Study name Parameter Time point HFNO Standard oxygen therapy NIV P
Bell et al Decrease in Borg score 2h 75% 55.8% .044
(n = 48) (n = 52)
Frat et al Dyspnea score 1h 29 (26) 40 (29) 43 (29) b.01
(n = 106) (n = 94) (n = 110)
% of patients with improvement 1h 75.6% 41.9% 58.3% b.001
in dyspnea score (n = 106) (n = 94) (n = 110)
Jones et al % of patients with improved Not mentioned 79.6% 71.4% Not mentioned
breathing (n = 94) (n = 64)
Rittayamai et al Dyspnea score 1h 2 (1.8) 3.8 (2.3) .01
(n = 20) (n = 20)
Lemiale et al Dyspnea VAS score 2h 3 (2-6) 3 (1-6) .87
(n = 52) (n = 48)
Stephan et al % of patients with dyspnea Day 1 56.6% (n = 396) 56.5% (n = 402) N.99
score improvement 1h 58.6% (n = 403) 65.8% (n = 404) .39
Table 4

Comfort score (mean [SD] or median [IQR]) or proportion of patients comfortable (%)

Study name Parameter Time point HFNO Standard oxygen therapy NIV P
Bell et al Comfort score 2h 4 (3-4) 3 (2-4) .035
(n = 48) (n = 52)
Frat et al Discomfort score 1h 29 (26) 40 (29) 48 (29) b.01
(n = 106) (n = 94) (n = 110)
Jones et al % of patients comfortable Not mentioned 74.2% (n = 94) 85.9% (n = 64) .08
Rittayamai et al Comfort score 1h 1.6 (1.7) 3.7 (2.4) .01
(n = 20) (n = 20)
Lemiale et al Discomfort VAS score 2h 3 (1-5) 3 (0-5) .88
(n = 52) (n = 48)
Stephan et al % of patients with good comfort Day 1 50.1% (n = 395) 49% (n = 399) N.99
1h 58.2% (n = 402) 55% (n = 397) .32
144 S. Maitra et al. / Journal of Critical Care 35 (2016) 138144
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