The Effect of High-Flow Nasal Cannula Oxygen

Therapy on Mortality and Intubation Rate in Acute

Respiratory Failure: A Systematic Review and
Meta-Analysis
Thalia Monro-Somerville, MBBS1; Malcolm Sim, MD2; James Ruddy, MBBS3; Mark Vilas, MBChB2;
Michael A. Gillies, MD1

Objective: High-flow nasal cannulae are used in adults with or

at risk of acute respiratory failure. We conducted a systematic
review and meta-analysis to evaluate the evidence for their use in
this setting.
Data Sources: Ovid Medline, Embase, and Cochrane Database of
Systematic Reviews.
Study Selection: Databases were searched for randomized controlled trials comparing administration of high-flow nasal cannulae
Department of Anaesthesia, Critical Care and Pain Medicine, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.
2
Department of Anaesthesia, Critical Care and Pain Medicine, Queen
Elizabeth University Hospital, Glasgow, United Kingdom.
3
Department of Anaesthesia, Critical Care and Pain Medicine, Monklands
General Hospital, Airdrie, United Kingdom.
All authors contributed equally to the study design, study conduct, and
preparation of the article. Drs. Monro-Somerville and Gillies take responsibility for the conduct of the study and the integrity of the results. All
authors read and approved the final article.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF
versions of this article on the journals website (http://journals.lww.com/
ccmjournal).
Dr. Monro-Somerville disclosed other support (Drs. Sim and Gillies are
Chief Scientists Office (Scotland) research fellows). Drs. Monro-Somerville, Sim, and Ruddy have received funding from Fisher-Paykel to attend
conferences. Dr. Sim received funding from Fisher and Paykel (no money
paid directly to Dr. Sim, but accommodation and travel were organized
for speaking at a respiratory CARE conference and for being a delegate
at another respiratory care conference). His institution received funding
from Fisher and Paykel (manufacturers of a high-flow nasal oxygen device
and Scottish Infection Research Network [small grant examining metabolomics in sepsis]). Dr. Ruddy disclosed other support (expenses paid to
present at CARE conference). Dr. Gillies institution received funding from
Chief Scientists Office (Scotland). Dr. Vilas disclosed that he does not
have any potential conflicts of interest.
Address requests for reprints to: Thalia Monro-Somerville, MBBS, Michael
A. Gillies, MD, Department of Anaesthesia, Critical Care and Pain Medicine,
Royal Infirmary of Edinburgh, Little France Crescent, Edinburgh, EH16 4SA,
United Kingdom. E-mail: tmonrosomerville@nhs.net; michael.gillies@ed.ac.uk
1

Copyright 2016 by the Society of Critical Care Medicine and Wolters

Kluwer Health, Inc. All Rights Reserved.
DOI: 10.1097/CCM.0000000000002091

Critical Care Medicine

with usual care (i.e., conventional oxygen therapy or noninvasive

ventilation) in adults with respiratory failure. The primary outcome
was hospital mortality; the rate of intubation and assessment of
delirium and comfort were secondary outcomes.
Data Extraction: One hundred forty-seven nonduplicate citations
were screened, 32 underwent full screening and data extraction, and 14 trials were eligible for inclusion in the review. Nine
trials were used in the meta-analysis, including a total of 2,507
subjects.
Data Synthesis: When high-flow nasal cannulae were compared
with usual care, there was no difference in mortality (high-flow
nasal cannulae, 60/1,006 [6%] vs usual care, 90/1,106 [8.1%])
(n=2,112; p=0.29; I2, 25%; fixed effect model: odds ratio,
0.83; 95% CI, 0.581.17) or rate of intubation (high-flow nasal
cannulae, 119/1,207 [9.9%] vs usual care, 204/1,300 [15.7%])
(n=2,507; p=0.08; I2, 53%; fixed effect model: odds ratio, 0.63;
95% CI, 0.371.06). A qualitative analysis of 13 studies on tolerability and comfort suggested that high-flow nasal cannulae are
associated with improved patient comfort and dyspnea scores.
Trial sequential analyses on primary and secondary outcomes
suggested that required information size was not reached.
Conclusions: No difference in mortality or intubation was detected
in patients with acute respiratory failure treated with high-flow
nasal cannulae compared with usual care. High-flow nasal cannulae seem well tolerated by patients. Further large randomized
controlled trials are required to evaluate their utility in this setting.
(Crit Care Med 2016; XX:0000)
Key Words: inhalation therapy; meta-analysis; oxygen; respiratory
failure

igh-flow nasal cannulae (HFNC) are an established

mode of oxygen therapy and have been used in neonatal and pediatric settings for over a decade. More
recently, HFNC have been used in adults with several systems
currently available. HFNC delivered via nasal cannulae can
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Monro-Somerville et al

deliver warmed, humidified oxygen with Fio2 of up to 1.0, a

maximum flow of 60L/min, and a temperature of 37C. Indications for its use include treatment of acute respiratory failure
(ARF) (15), acute pulmonary edema (6), chronic disease (7, 8),
preoxygenation (9), maintenance of oxygenation during airway
instrumentation (10), prevention and treatment of postoperative respiratory failure (1116), and palliation (17).
Several potential advantages of HFNC over conventional
oxygen therapy (COT) and noninvasive ventilation (NIV) have
been proposed but remain to be proven. HFNC can deliver a
constant Fio2 through a range of respiratory dynamics (4, 18).
The high-flow rates used may generate positive end-expiratory
pressure (range, 35cm H2O) (19). Other theories by which
HFNC may improve oxygenation and respiratory mechanics
are based on animal or neonatal models. These include washout of nasopharyngeal dead space (20), tracheal insufflation
during the inspiratory pause (21), improving the efficiency of
tidal ventilation, reduced upper airway resistance, and reduced
work of breathing (3, 23). Humidification of inspired gas prevents drying of respiratory secretions, improves mucociliary
sputum clearance, and aids expectoration (3, 24). Reduced
interruption to normal activity may also increase patient compliance with oxygen therapy and thus improve outcome (1,
23). Potential disadvantages of the therapy might include oxygen toxicity (25) and delayed intubation (11, 26).
Despite theoretical therapeutic advantages and rapid, widespread adoption of this technology in critical care, there remains
a paucity of clinical trial data to support the use of HFNC in
adults with ARF. We conducted a systematic review and metaanalysis to evaluate the effect on mortality, intubation, and tolerability of HFNC in adults with ARF of any etiology.

METHODS
The research question was formulated using the Population, Incidence, Comparator, Outcome model (Supplemental Table1,
Supplemental Content 1, http://links.lww.com/CCM/C176).
Search Strategy
The study protocol was published on the International Prospective Register of Systematic Reviews website (http://www.
crd.york.ac.uk). Ovid Medline, Embase, and Cochrane Database of Systematic Reviews were searched for suitable studies
using a structured search strategy: high-flow nasal oxygen.mp
or nasal high flow.mp or high-flow nasal oxygen therapy.mp
or high-flow nasal prongs.mp or nasal high-flow oxygen.mp
or high-flow nasal cannula.mp or humidified high-flow nasal
cannula.mp or heated and humidified high-flow nasal oxygen.
mp or Optiflow.mp and respiratory insufficiency/or respiratory failure.mp or oxygen inhalational therapy.mp or acute
respiratory distress syndrome.mp or respiratory distress syndrome, adult/or ventilation.mp or ventilation/or dyspnea.
Search results were limited to randomized controlled trials
(RCTs) in adults, reported in English language. Authors and
research teams from commercial suppliers were contacted to
ascertain if they were aware of other studies not captured by
the search strategy; conference proceedings and bibliographies
2

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were also reviewed. Four further studies met inclusion criteria for this systematic review or meta-analysis. The literature
search was conducted independently by two authors (T.M.S.,
M.S.). Disparities in the literature review were resolved by
consensus of all authors. Search strategy and analysis were carried out using the Preferred Reporting Items for Systematic
Review and Meta-Analysis statement 2009 (27).
Study Selection Criteria and Quality Assessment
Search results were reviewed and evaluated independently by
two authors (T.M.S. and M.A.G.). The following criteria were
used for inclusion in our meta-analysis: RCTs of adult patients
with respiratory failure of any cause, HFNC versus any other
oxygen delivery modality including COT or NIV (referred
to as usual care), and complete data available on any of the
outcomes. Studies were excluded if not published in English,
crossover studies, nonhuman experimental studies, or lack of
complete data in the outcomes of interest. The primary outcome for the meta-analysis was hospital mortality, and secondary outcome was tracheal intubation. The following subgroups
were analyzed: postoperative respiratory failure, postextubation
respiratory failure, ARF of medical origin, and intubation rates
when HFNC was compared with patients treated with COT only
or NIV only. In addition, any randomized trials reporting incidence of delirium and comfort scores were included in a qualitative assessment of patient comfort and tolerability. Studies
were screened for methodological quality using the Cochrane
Collaboration Risk of Bias tool, an established method of assessing methodological quality and internal validity of studies to be
included in meta-analysis (28). The overall risk of bias was considered low only if all components were rated as having a low
risk of bias. Disagreements on studies to be included in the final
analysis were resolved by consensus of the whole study group.
Grading of Quality of Evidence
We used the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) Working Group methodology to assess the overall quality of the evidence for the primary
and secondary outcomes in the following domains: inconsistency, indirectness, imprecision, and publication bias. This was
classified as very low, low, medium, and high (29).
Data Extraction
Data extraction was undertaken by two authors (M.A.G.,
T.M.S.) for each eligible study and included author, year of publication, patient group studied, number of subjects, modality of
comparator oxygen delivery, commercial support, hospital mortality, and incidence of reintubation. A qualitative assessment of
patient tolerability and comfort was made where reported.
Statistical Analysis
Statistical analysis was carried out using RevMan Review Manager, version 5.3, Nordic Cochrane Review Centre, Copenhagen,
Denmark) and Trial Sequential Analysis (TSA) Program version 0.9 (Copenhagen Trial Unit, Denmark; http://www.ctu.dk/
tsa). Evidence of statistical heterogeneity between studies was
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Online Review Article

assessed by chi-square and I2tests; 25%, 50%, and 75% indicated the presence of low, moderate, and high between-trial heterogeneity, respectively. A p value of 0.1 was used to denote the
statistical significance of heterogeneity. The funnel plot method
was used to assess for evidence of publication bias for any of
the outcomes, either primary or secondary. Dichotomous outcomes were expressed as odds ratio (OR) with 95% CIs. For all
analyses performed, if no significant heterogeneity was noted,
fixed effect model (FEM) analysis using the Mantel-Haenszel
method was used; otherwise, a random-effects model analysis
was undertaken using the DerSimonian-Laird method. To assess
for the possibility of random error due to paucity of available
data, we used TSA. In brief, TSA uses methodology developed
for repeated significance testing in large RCTs and estimates
that the meta-analysis is of adequate information size (IS),
that is, contains sufficient patients and events to draw reliable
conclusions. Traditional meta-analysis software (e.g., RevMan)
does not provide this information. If the cumulative z score for
included trials crosses the monitoring boundary, then no further
Table 1.

trials are needed. If this does not occur, the available evidence is
not sufficient to draw a firm conclusion. We included TSA for
the outcomes of mortality and intubation.

RESULTS
Study Selection
The process for literature search and study selection is presented
in Figure 1. One hundred forty-seven nonduplicate citations
were screened; of which, 32 were available in full text and underwent full screening. Fourteen trials were eligible for inclusion
(11, 12, 1417, 23, 3036), and nine trials were used in the metaanalysis, including 2,507 subjects (Fig.1) (11, 15, 16, 3035).
Thirteen trials were used in the qualitative assessment of patient
comfort and tolerability (11, 12, 1417, 23, 3034, 36).
Characteristics of Included Studies
The characteristics of the included studies are summarized in
Table 1. Of note, five trials were multicenter (11, 16, 30, 31, 35),

Studies Included in Systematic Review and Meta-Analysis

Study

Design

Setting

Population

Reports
Included
Reports Reports Comfort Commercial in MetaComparator Multicentre Mortality Intubation Score
Support
Analysis

Hernandez
etal (35)

RCT

General Postextubation
ICU

527

FM

Yes

Yes

Yes

No

Yes

Yes

Rittayami
etal(14)

RCT

ED

ARF

40

FM/nasal
cannula

No

No

Yes

Yes

Yes

Yes

Bell et al (31) RCT

ED

ARF

100

FM

Yes

No

Yes

Yes

Yes

Yes

Corley
et al (34)

RCT

Cardiac
ICU

Postextubation,
body mass
index > 30

155

FM

No

No

Yes

No

Yes

Yes

Lemaile
etal(32)

RCT

General ARF immuno

ICU
compromised
patients

100

FM

No

Yes

Yes

Yes

Yes

Yes

Stephan
etal(16)

RCT

Cardiac
ICU

Postextubation

830

NIV

Yes

Yes

Yes

Yes

Yes

Yes

Frat et al (30) RCT

Medical
ICU

ARF

310

FM/NIV

Yes

Yes

Yes

Yes

Yes

Yes

Maggiore
et al (11)

General Postextubation
ICU

105

FM

Yes

Yes

Yes

Yes

Yes

Yes

RCT

Schwabbauer Crossover Medical

et al (36)
ICU

ARF

14

FM/NIV

No

No

No

Yes

Yes

No

Rittayami
etal(33)

Crossover Medical
ICU

Postoperative
extubation

17

FM

No

No

Yes

Yes

Yes

Yes

Parke
et al (15)

RCT

Postoperative
extubation

340

FM

No

Yes

Yes

No

Yes

Yes

Hui et al (17) Crossover Oncology Oncology

ward
patients

30

FM/NIV

No

No

No

Yes

Yes

No

Cuquemelle
et al (23)

Crossover Medical
ICU

ARF

30

FM

No

No

Yes

Yes

Yes

No

Tiruvoipati
et al (12)

Crossover Medical
ICU

Postextubation

50

FM

No

Yes

No

Yes

Yes

No

Cardiac
ICU

ARF=acute respiratory failure, ED=emergency department, FM=face mask, NIV, noninvasive ventilation, RCT=randomized controlled trial.

Critical Care Medicine

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Monro-Somerville et al

blinding and inconsistency. A

summary of the findings and
quality of the analysis is provided in Table 2.
Characteristics of Excluded
Studies
Twenty-three studies were available in full text and were excluded
following the review, and six were
RCTs (4, 10, 3740). One did
not report primary or secondary outcomes (4), one studied
healthy volunteers (37), and four
studied HFNC during airway
instrumentation (10, 37, 39, 40).
Seventeen trials were observational (supplemental file, Supplemental Content 1, http://
links.lww.com/CCM/C176)
(13, 5, 8, 13, 24, 26, 4149).

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram detailing search
strategy.

seven European (11, 16, 23, 30, 32, 35, 36), four Australian
(12, 15, 31, 34), one American (17), and two conducted in
Thailand (14, 33). Five trials reported intubation as a primary
outcome (16, 3032, 35) and four as a secondary outcome
(11, 15, 33, 34). Patient comfort was recorded as a secondary
outcome in 11 studies (11, 12, 1416, 23, 3033, 36). Dyspnea
was reported as a primary outcome in three trials (14, 31, 33)
and as a secondary outcome in six studies (16, 17, 30, 32, 34, 36).
In three studies, subjects were postoperative cardiothoracic
patients (15, 16, 34), four trials concerned subjects extubated
after ventilation for acute illness (11, 12, 14, 35), and eight studies involved patients with new ARF (17, 23, 3033, 35, 36). All
were conducted within the ICU and were discontinued when
the patient was discharged from critical care. Funnel plots did
not demonstrate the evidence of publication bias for primary
or secondary outcomes (supplemental file, Supplemental Content 1, http://links.lww.com/CCM/C176). The GRADE quality
evidence was thought to be low, mainly as a result of lack of
4

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Primary Outcome
Mortality data were available in five studies included
in the meta-analysis, including a total of 2,112 subjects
(11, 15, 16, 30, 35). Of the
1,006 patients treated with
HFNC, 60 (5.9%) died, compared with 90 of the 1,106
(8.1%) treated with usual
care. No significant difference
was demonstrated between
groups (p=0.29; I2 25%; FEM:
OR, 0.83; 95% CI, 0.581.17)
(Fig. 2).

Secondary Outcome
Intubation data were available in nine studies included in the
meta-analysis, including a total of 2,507 subjects (11, 15, 16, 30
35). Of the 1,207 patients treated with HFNC, 119 (9.9%) were
intubated compared with 204 of the 1,300 (15.7%) receiving
conventional oxygen therapies or NIV. Overall, there was no significant difference in intubation rates between groups (n=2,507;
p=0.08; I2, 53%; FEM: OR, 0.63; 95% CI, 0.371.06) (Fig. 3).
Post Hoc Analyses
Subgroup analysis showed no difference in the intubation
rate when restricted to postoperative patients (n=1,325;
p=0.91; I2, 14%; FEM: OR, 1.02; 95% CI, 0.701.50) (15, 16,
34). Restriction to postextubation patients showed no difference in the intubation rate (n=1,957; p=0.16; I2, 70%; FEM:
OR, 0.52; 95% CI, 0.211.29) (11, 15, 16, 34, 35). There was
no evidence of a positive effect in the subgroup of patients
with medical respiratory failure. This was defined as new
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Online Review Article

Table 2.

GRADE Table of Quality of Evidence of Articles Included in the Meta-Analysis

Quality Assessment

No. of
Studies

Study
Design

No. of Patients

Effect

High-Flow Standard
Risk of
Other
Nasal
Oxygen
Bias Inconsistency Indirectness Imprecision Considerations Cannulae Therapies

Relative
OR,
(95% CI)

Absolute
(95% CI) Quality

Mortality
5

Randomized Seriousa Not serious

control
trials

Not serious

Seriousb

None

60/1,006 90/1,106
0.83
13 fewer

(6.0%)
(8.1%) (0.581.17) per 1,000 LOW
(from 13
more to
33 fewer)

Not serious

Not serious

None

119/1,207 204/1,300
0.64
50 fewer

(9.9%)
(15.7%) (0.31.07)
per 1,000 LOW
(from 9
more to
91 fewer)

Intubation
9

Randomized Seriousa
control
trials

Seriousc

OR=odds ratio.
a
Unblinded intervention.
b
Wide CI.
c 2
I , 51%.

Figure 2. Forrest plot comparing mortality rates in patients treated with high-flow nasal cannulae (HFNC) compared with usual care.

onset respiratory failure in patients in the ward or emergency

department (n=550; p=0.1; I2, 0%; FEM: OR, 0.69; 95% CI,
0.441.08) (3033) (supplemental file, Supplemental Content
1, http://links.lww.com/CCM/C176).
When restricted to comparing rate of intubation in patients
receiving HFNC with COT only (i.e., conventional facemask or
nasal cannula), a significant difference was observed (n=1,567;
p=0.0008; I2, 35%; FEM: OR, 0.52; CI, 0.360.76) (11, 15, 3035).
When restricted to comparing rate of intubation in patients receiving HFNC with NIV only, no difference was observed (n=1,046;
p=0.33; I2, 58%; FEM: OR, 0.85; CI, 0.621.17) (16, 30).
Comfort and Tolerability
Nine studies reported the effect HFNC on dyspnea compared with conventional modalities (14, 16, 17, 3034, 36).
Critical Care Medicine

Assessment of dyspnea was made using a combination of

visual analog scale (VAS), visual numerical scale (VNS), fivepoint Likert Scale, and Borg Cr10 scales. Four studies reported
significantly reduced dyspnea when HFNC was compared
with using a facemask (14, 30, 31, 33); another showed reduced
dyspnea scores with conventional treatment compared with
HFNC (34). One study showed improvement when HFNC was
compared with NIV (36). Two studies showed similar dyspnea
scores when HFNC was compared with either modality (16,
32), and two studies showed reduced dyspnea scores compared
with FM, although they did not reach significance (17, 36).
Eleven studies reported an assessment of comfort using VNS
or VAS (11, 12, 1416, 23, 3033, 36). Two studies showed similar comfort scores compared with NIV (16) or facemask (32).
Three studies showed a trend toward improved comfort, which
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Monro-Somerville et al

Figure 3. Forrest plot comparing intubation rates in patients treated with high-flow nasal cannulae (HFNC) compared with usual care. M-H = Mantel-Haenzel.

did not meet statistical significance (12, 14, 36). Five studies
showed significantly improved comfort scores compared with
FM (11, 23, 30, 31, 33) or NIV (30, 36); another showed a significant improvement in tolerability of HFNC compared with
conventional oxygen (12). One showed facemask to be superior to HFNC (15). No studies included in the final analysis
used delirium as an outcome.
TSA
TSA was undertaken for the outcomes of mortality and intubation based on a relative risk reduction of 0.26 and 0.37, respectively, a type 1 error of 0.05 and a type 2 error of 0.8. For each
outcome, neither required IS (mortality, n=6,899; intubation,
n=4,018) nor boundaries for benefit, harm, or futility were
reached (supplemental file, Supplemental Content 1, http://
links.lww.com/CCM/C176).

DISCUSSION
The principal finding of this systematic review and metaanalysis is that no significant difference in mortality or intubation rate was detected in adult patients with ARF treated with
HFNC, when compared with usual care defined as COT or
NIV. The required IS was not reached using TSA; hence, more
studies are needed to answer this question definitively. A qualitative analysis on dyspnea, tolerability, and comfort suggested
that HFNC is at least equivalent to usual care, with the majority of studies suggesting improved dyspnea and comfort scores.
In post hoc analyses, there was no difference in intubation rates
when restricted to the perioperative subgroup, post extubation,
or new respiratory failure subgroups, or when compared with
NIV. A significant difference in the intubation rate was demonstrated when HFNC was compared with conventional oxygen
delivery alone (p=0.0008), although as a post hoc analysis, this
finding must be interpreted with caution.
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To our knowledge, this is the first systematic review and metaanalysis to evaluate whether the use of HFNC in patients with
ARF has an effect on mortality or intubation rate. Despite the
lack of high-quality trial data, HFNC is considered by many to be
superior to conventional methods of oxygen delivery and enjoys
widespread use (50). Much of the current evidence for the use
of HFNC has been conducted in pediatric patients or after adult
cardiothoracic surgery, and these studies may lack external validity for patients with acute or postoperative respiratory failure in
the general population. Observational and RCT data support
the assumption that HFNC is at least equivalent to conventional
oxygen therapies or NIV and has shown improvement in physiologic outcomes, and there is no evidence of harm and improved
patient comfort (11, 30). The largest RCT in adults with ARF did
not demonstrate a reduction in the intubation rate when compared with NIV or COT in adult patients with ARF (30). The
study did show significant reduction in duration of mechanical
ventilation and 90-day mortality in the HFNC group as secondary outcomes. A post hoc analysis suggested reduced intubation
rate in the subgroup with severe hypoxemic respiratory failure
(Pao2/Fio2 ratio, < 200mm Hg) treated with HFNC. One study
included time to intubation as a secondary outcome and found
no difference in outcomes (35). Other studies have suggested that
time to intubation may be longer in patients treated with HFNC
compared with COT (15) but similar in patients treated with NIV
(16, 30). This could reflect the existing controversy regarding the
use of NIV in ARF; that prolonged therapy results in delayed
intubation, leading to increased mortality in some patients (51,
52). Similar results have been reported regarding the prolonged
use of HFNC (26). The Hernandez protocol limited HFNC to
24 hours post extubation, based on the suggestion that a delay in
intubation of more than 48 hours may be detrimental (26, 35).
Other commentators have raised the possibility of oxygen toxicity as another undesirable feature of therapy with HFNC (25).
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Online Review Article

The strengths of this study include prospective publication

of study protocol, rigorously conducted systematic review, and
utilization of conservative and validated statistical methods.
Potential weaknesses lie in the low quality of the included trials,
in particular the possibility of bias because of the unavoidable
absence of blinding in all trials. The comparability of patients
with postoperative respiratory failure with those suffering ARF
from other causes may be debatable, and the findings of our
analysis have suggested that there may be clinically significant
differences between these groups. The duration of the treatment, specified dosing and titration of oxygen concentrations,
and flow rates differed between studies, as did the prescribed
respiratory variables, and is another potential source of bias
in this analysis. There was no consistent reporting of patient
comfort, dyspnea, and tolerance, necessitating a qualitative
evaluation. Finally, all nine studies included in this meta-analysis received sponsorship or equipment from Fisher and Paykel
Healthcare, although all articles state that the trial design, data
analysis, and preparation of the article were independent of
commercial interference.
Equipoise remains for future, adequately powered trials of
this therapy. Findings of this analysis suggest that these trials
might be most appropriately directed at patients with ARF of
medical or nonpostoperative etiology, perhaps with comparison
with COT alone. NIV has not been conclusively demonstrated
to be beneficial in ARF, with more established evidenced for
use in exacerbation of chronic obstructive pulmonary disease,
cardiogenic pulmonary edema, and respiratory failure in immunosuppressed patients (51, 52). Future studies could also investigate the incidence of nosocomial pneumonia and delirium in
patients treated with HFNC therapy. It is also possible that the
improved tolerability of HFNC, compared with conventional
therapy, makes it a more consistent and reliable means of delivering high concentrations of inspired oxygen and benefits stem
from this alone. Finally, a safe duration of HFNC therapy should
be defined, after which if respiratory function does not improve,
intubation and ventilation should be considered.

CONCLUSIONS
A systematic review and meta-analysis investigating HFNC in
adult patients treated for ARF did not demonstrate a reduction
in mortality associated with its use. TSA suggests that required
IS was not reached, and thus, further trials are required to
answer this question definitively. A qualitative analysis suggests
that this therapy was well tolerated and may improve dyspnea
scores and patient comfort. Future trials should identify the
populations most likely to benefit from this treatment and
define safe limits of therapy.

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