247
Reviews on Recent Clinical Trials
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Reviews on Recent Clinical Trials, 2019, 14, 247-260
SYSTEMATIC REVIEW ARTICLE
ISSN: 1574-8871
eISSN: 1876-1038
High Flow Through Nasal Cannula in Stable and Exacerbated Chronic
Obstructive Pulmonary Disease Patients
BENTHAM
SCIENCE
Andrea Bruni1,#, Eugenio Garofalo1,#, Gianmaria Cammarota2, Paolo Murabito3, Marinella Astuto3,
Paolo Navalesi1, Francesco Luzza4, Ludovico Abenavoli4 and Federico Longhini1,*
1
Department of Medical and Surgical Sciences, Intensive Care Unit, University Hospital Mater Domini, Magna Graecia
University, Catanzaro, Italy; 2Anesthesia and Intensive Care, “Maggiore della Carità” Hospital, Novara, Italy;
3
Department of Anesthesia and Intensive Care, A.O.U. "Policlinico -Vittorio Emanuele", Catania, Italy; 4Department of
Health Sciences, University of Catanzaro "Magna Graecia", Viale Europa, 88100 Catanzaro, Italy
Abstract: Background: High-Flow through Nasal Cannula (HFNC) is a system delivering heated
humidified air-oxygen mixture at a flow up to 60 L/min. Despite increasing evidence in hypoxemic
acute respiratory failure, a few is currently known in chronic obstructive pulmonary disease (COPD)
patients.
Objective: To describe the rationale and physiologic advantages of HFNC in COPD patients, and to
systematically review the literature on the use of HFNC in stable and exacerbated COPD patients,
separately.
ARTICLE HISTORY
Received: April 29, 2019
Revised: June 19, 2019
Accepted: June 20, 2019
DOI:
10.2174/1574887114666190710180540
Methods: A search strategy was launched on MEDLINE. Two authors separately screened all potential references. All (randomized, non-randomized and quasi-randomized) trials dealing with the use
of HFNC in both stable and exacerbated COPD patients in MEDLINE have been included in the review.
Results: Twenty-six studies have been included. HFNC: 1) provides heated and humidified airoxygen admixture; 2) washes out the anatomical dead space of the upper airway; 3) generates a small
positive end-expiratory pressure; 4) guarantees a more stable inspired oxygen fraction, as compared
to conventional oxygen therapy (COT); and 5) is more comfortable as compared to both COT and
non-invasive ventilation (NIV).
In stable COPD patients, HFNC improves gas exchange, the quality of life and dyspnea with a reduced cost of muscle energy expenditure, compared to COT. In exacerbated COPD patients, HFNC
may be an alternative to NIV (in case of intolerance) and to COT at extubation or NIV withdrawal.
Conclusion: Though evidence of superiority still lacks and further studies are necessary, HFNC
might play a role in the treatment of both stable and exacerbated COPD patients.
Keywords: Chronic obstructive pulmonary disease, high flow nasal cannula, hypercapnia, non-invasive ventilation, oxygen,
positive-pressure respiration, respiratory insufficiency, respiratory therapy.
1. INTRODUCTION
High-Flow through Nasal Cannula (HFNC) is an innovative system that delivers heated humidified air-oxygen mixture, with an inspiratory fraction of oxygen (FiO2) from 21 to
100%, at flow up to 60 L/min [1, 2]. The flow is generated
by an air-oxygen blender or a dedicated machine with a turbine; the flow goes through an active heated humidifier and
*Address correspondence to this author at the Intensive Care Unit, University Hospital Mater Domini, Department of Medical and Surgical Sciences,
Magna Graecia University, Catanzaro, Italy; Tel: +393475395967;
Fax: +3909613647313; E-mail: longhini.federico@gmail.com
#
These authors contributed equally to this work.
1876-1038/19 $58.00+.00
it is delivered to the patient through a single branch with a
large bore nasal cannula at its distal end.
Increasing evidences encourage HFNC use in the daily
clinical practice. For instance, in those patients with hypoxemic Acute Respiratory Failure (ARF) of varying etiologies,
HFNC decreases: 1) oxygen therapy risk of escalation of
oxygen therapy, defined as crossover to HFNC, or switch to
non-invasive (NIV) or invasive mechanical ventilation
(iMV); 2) the risk of tracheal intubation without impacting
mortality and Intensive Care Unit (ICU) or hospital lengths
of stay [3]. If on one hand there is a strong evidence that
supports HFNC use in patients with hypoxemic ARF, on the
© 2019 Bentham Science Publishers
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Reviews on Recent Clinical Trials, 2019, Vol. 14, No. 4
other hand it is not nowadays well known in those patients
with chronic or acute-on-chronic respiratory failure.
Chronic Obstructive Pulmonary Disease (COPD) is the
fourth leading cause of chronic morbidity in the world [4].
COPD history may present exacerbations, which are characterized by worsening of respiratory symptoms, sometimes
requiring hospitalization [4]. COPD patients are invited to
smoking cessation and pharmacological treatments (such as
bronchodilators) are generally required. In the most severe
patients with severe resting chronic hypoxemia, the prescription of long-term oxygen therapy (LTOT) (>15 hours/day) is
needed [4]. Indeed, LTOT increases patients’ survival rate.
In patients with severe chronic hypercapnia and a history of
hospitalization for hypercapnic ARF, long-term NIV decreases mortality and prevent re-hospitalization [4]. However, both LTOT and NIV are affected by poor tolerance, leading to low adherence to the treatment.
The easiness of application, the improved comfort, together with some physiological effects and advantages,
would make possible the use of HFNC in stable COPD patients at home, during rehabilitation and even during hospitalization for episodes of exacerbation.
In this systematic review, we describe the rationale and
physiologic possible advantages in COPD patients. In addition, we analyze the current literature on HFNC use in stable
and exacerbated COPD patients, separately.
2. METHODS AND SEARCH STRATEGY
2.1. Search Methods for Identification of Studies
We have performed an electronic search of Medline from
inception until April 9, 2019 with no language restrictions.
Controlled vocabulary terms (when available), text words,
and keywords have been variably combined. Blocks of terms
per concept have been created.
We have used the following search strategy: “("respiratory failure" [MeSH Terms] OR "acute respiratory failure" [All
Fields] OR "respiratory insufficiency" [All Fields] OR "respiratory failure" [All Fields] OR "COPD" [All Fields] OR
"Chronic Obstructive Pulmonary Disease" [All Fields] OR
"chronic respiratory failure" [All Fields] OR "hypercapnic"
[All Fields] OR “Hypercapnic Acute Respiratory Failure”
[All Fields] OR "acute no chronic respiratory failure" [All
Fields]) AND ("high flow nasal oxygen" [All Fields] OR
"high-flow nasal oxygen" [All Fields] OR "high flow nasal
cannula" [All Fields] OR “high-flow nasal cannula" [All
Fields] OR "high flow oxygen" [All Fields] OR "high-flow
oxygen" [All Fields] OR “High-Flow Oxygen Therapy” [All
Fields])”. This systematic review reports findings according
to PRISMA guidelines.
2.2. Studies Selection
Studies have been considered only if including adult
COPD patients undergoing HFNC due to any reason (domiciliary support, rehabilitation, support therapy for exacerbation or weaning). All studies dealing with the potential advantageous mechanisms of HFNC in COPD patients have
Bruni et al.
been all considered for an introductive narrative review. In
the second part, we have included randomized or non-RCTs
(including crossover design) and observational studies comparing HFNC with a control group (standard oxygen therapy,
non-invasive ventilation). The studies have been classified
according to the stability or exacerbation of the treated disease.
Titles and abstracts have been independently screened by
two authors (AG and EG) according to the inclusion criteria
and the full texts of the potentially relevant reports have been
retrieved. The full-text reports have been independently examined by two authors (AG and EG). We have included all
studies dealing with HFNC in stable or exacerbated COPD in
different settings. We have excluded only reviews, editorials
and commentaries. Included studies have been recorded using a Microsoft Excel standardized report form. All disagreements have been resolved by discussion and referral to a
third author (FL) if necessary.
2.3. Risk of Bias Assessment
The methodological quality of included parallel-group
RCTs have been assessed using Review Manager software
(RevMan 5.3; Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). Randomized and nonrandomized crossover studies have been assessed according to a
modified version of the checklist proposed by Ding et al. [5].
We have evaluated all studies for randomized sequence generation, allocation concealment, blinding of participants and
personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other bias.
3. RESULTS
The electronic search has identified 363 potentially relevant studies (358 from MEDLINE and 5 from references
retrieving). Thirty-one full-text articles have been assessed
for eligibility, and 26 have been considered relevant for this
review and included in the qualitative synthesis. Detailed
description of the selection process flow is provided in Fig.
(1). Selected studies included a mean (standard deviation)
patients sample size of 73 (98), ranging from 12 to 321 patients; the average age was 72.8 (2.9) years.
3.1. Potential Advantageous Mechanisms of HFNC in
COPD Patients
3.1.1. Heated Humidification
The epithelium of the respiratory tract acts as a fragile interface between the respiratory system and the air. A thin
layer of fluid, composed of an aqueous and a mucous (Gel)
films, covers and protects the epithelium. The presence of
the Gel film assures a correct motion of the cilia and the
transport of the mucus from the lungs to the airways opening. The beat frequency depends on the temperature and at
37°C it is around 750 beats/min.
In healthy individuals, the upper respiratory tract provides a warm, humid environment that plays a nonspecific
defense function and facilitates the mucociliary movement of
the normal airway epithelium [2]. Atmospheric air is at about
Identification
High Flow Through Nasal Cannula in COPD
Reviews on Recent Clinical Trials, 2019, Vol. 14, No. 4
Records identified through
database searching
(n = 358)
249
Additional records identified through
other sources
(n = 5)
Records screened
(n = 363)
Records excluded
(n = 332)
Eligibility
Full-text articles assessed for
eligibility
(n = 31)
Full-text articles excluded,
with reasons
(n = 5)
 studies not reporting
on HFNC (n = 3)
 review (n = 2)
Included
Screening
Records after duplicates removed
(n = 363)
Studies included in
qualitative synthesis
(n = 26)
Fig. (1). Flow Diagram. Study flow diagram according to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols
recommendations.
20°C, with an AH = 10 mg/L and RH of 55-60%. Its passage
through the airways and bronchi permits full saturation of
water vapor [100% relative humidity (RH), absolute humidity (AH) = 44 mg/L] and heating at 37°C which mainly occurs in the nose. However, the point (isothermal saturation
limit) where the gas gets fully heated (37°C) and humidified
(44 mg/L), is further deep and usually close to the 4th or 5th
bronchial generation [6]. Such conditions are optimal to keep
a normal function of the airway epithelium, and every little
modification might impair the epithelial cell role [7].
The administration of inadequately conditioned medical
gases, such as during conventional oxygen therapy (COT) or
NIV, shifts the isothermic saturation boundary farther deepens the bronchial tree, affecting the ciliary motion, damaging
the respiratory tract epithelial cell and reducing the water
content of the bronchial secretions [8-10]. In this regard,
active heated humidification of gases increases the gas temperature and humidity, and reduces the inflammatory responses associated to iMV, epithelial cell cilia damage, and
airway water loss [11].
HFNC provides temperature and humidity-controlled gas
to the airway. In an in vitro study on cultured human airway
epithelial cells, Chidekel et al. have showed that humidification was beneficial to preserve the cellular structure and
function, and to reduce airway epithelial inflammation, when
compared to cells exposed to a dry condition over an 8-hour
exposure time. These benefits were higher with a temperature at 37°C and the RH at 90%, as provided by a HFNC
system [12]. In fourteen patients with idiopathic bronchiectasis, provision of heated (37°C) and humidified (44 mg/L) air
for 3 hours per day for 7 consecutive days resulted in significant enhancement of mucus clearance, measured by the deposition of the radio-pulmonary aerosols (99 mTc), as compared with baseline assessment [13]. In another single-center
study, 108 patients with COPD or bronchiectasis have been
randomized to receive for 1 year or HFNC (fully saturated at
37°C with a flow of 20-25 L/min) or standard therapy [14].
Despite a short (1.6 hours/day) daily application, HFNC reduced the exacerbation frequency by 19%, the number of
exacerbation days by 54% and prolonged the time to first
exacerbation from 27 to 52 days [14]. These data suggest
that keeping the airway humidified could ameliorate the mucociliary clearance and cough effectiveness, reducing the
accumulation of secretions in deeper airway and, potentially,
diminishing the risk of exacerbations and also hospital or
ICU acquired infections, such as ventilator-associated pneumonia and non-ventilator ICU-acquired pneumonia [10].
3.1.2. Anatomical Dead Space Washout
The anatomical dead space is the volume of air located in
the segments of the respiratory tract responsible for conduct-
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Reviews on Recent Clinical Trials, 2019, Vol. 14, No. 4
ing air from airways opening to the alveoli, without acting in
the process of gas exchange. Dead space includes the upper
airways, trachea, bronchi, and terminal bronchioles. In
healthy adults, the dead space is normally estimated at
2mL/kg of body weight, which consists in the 30% of the
tidal volume.
HFNC determines a wash out effect from carbon dioxide
(CO2) of the pharyngeal dead space. Moller et al. have assessed the CO2 wash out effect by HFNC at different flows
and respiratory rate in a 3D upper airway model; the investigators used a radioactive 81mKr-gas tracer and a gamma camera to detect its distribution in the upper airway model. The
clearance of tracing gas from upper airway model had a linear and a strong relationship with the flow applied by the
HFNC; in particular, every increment of 1 L/min of the flow
applied through HFNC determined a 1.8 ml/s increase of the
clearance in the nasal cavities. Furthermore, the wash out
effect was also time dependent: the lower was the respiratory
rate (and therefore longer the expiratory time), the higher
was the wash out effect [15]. In particular, CO2 elimination
was greater and more precocious in the nasal compartment
rather than in the pharyngeal sections [15].
Clearance from CO2 of the nasal cavity (40-50 ml in
healthy adults) comprises at least 30% of the anatomical
dead space in adults [16]. Therefore, the CO2 wash out effect
is potentially relevant for patients with an incremented ratio
between dead space and tidal volume, such as in COPD patients with exercise intolerance [17]. It should be also mentioned that, while interfaces for NIV, or oxygen masks are
characterized by an additional instrumental dead space,
HFNC does not [2].
In 11 stable COPD patients, Braunlich et al. have reported that HFNC at a flow of 20 L/min reduce the arterial partial pressure of CO2 (PaCO2) to a similar extent to NIV [18].
More recently, in 14 post-extubation COPD patients recovering from an exacerbation [19] and in 30 exacerbated COPD
patients at NIV discontinuation [20], HFNC significantly
have decreased the respiratory drive and work of breathing,
as compared to COT. In both studies, CO2 wash out was advocated as one of the two mechanisms to decrease the diaphragmatic workload, together with the generation of small
amounts of positive end-expiratory pressure (PEEP) [19-20].
3.1.3. “PEEP” Effect
In healthy subjects during unassisted spontaneous breathing, end-expiratory pharyngeal pressure is about 0.3 and 0.8
cmH2O, with open and closed mouth, respectively [21-23].
Compared to unassisted spontaneous breathing, HFNC generates greater pharyngeal pressure during expiration, while it
drops to zero during inspiration [22]. Similar findings have
also been reported by Parke et al. in 15 patients scheduled
for elective cardiac surgery [24] and by Braunlich et al. in 28
patients with stable COPD or idiopathic pulmonary fibrosis
[25]. The pressure generated by HFNC depends on the flow
delivered to the patient and the nasal prongs size in relation
to the nostrils [24, 26]. Ritchie et al. have also suggested that
the high flow delivered by HFNC acts as an expiratory resistance to patient’s exhalation, causing the “PEEP” effect
Bruni et al.
[21]. Ritchie et al. [21], Mundel et al. have also hypothesized that the augmentation of expiratory resistance by
HFNC could resemble also the pursed-lip breathing pattern
adopted by COPD patients, which is a strategy aimed to diminish the respiratory rate and to prolong the expiratory
time, finally resulting in a reduction of expiratory flow limitation and dynamic hyperinflation [27].
The “PEEP” effect is recommended as a mechanism to
improve end-expiratory lung volume and oxygenation in
healthy volunteers [28], in post-cardiac surgical patients
[29], in patients with hypoxemic ARF [3, 30] and after extubation [31]. In patients with chronic respiratory disorders,
such as COPD, the application of external PEEP through
HFNC may be of help in case of the presence of dynamic
lung hyperinflation and intrinsic PEEP. Indeed, the application of an external PEEP through NIV, to counteract intrinsic
PEEP, reduces the work of breathing in COPD patients [32].
Compared to COT, HFNC has also been shown to reduce the
respiratory muscle effort in both stable COPD patients [33]
and in those recovering from an episode of exacerbation
[20]. However, it should be noted that both studies did not
directly assess the amounts of intrinsic PEEP and this hypothesis about HFNC remains to be verified.
3.1.4. Provision of Stable Inspired Oxygen Fraction (FiO2)
When assessing oxygenation through arterial blood gases, it is essential to know FiO2, to compute the ratio between
the arterial partial pressure of oxygen (PaO2) and FiO2
(PaO2/FiO2). Nasal prongs and masks provide oxygen to a
patient as expressed in L/min, and the FiO2 cannot be estimated, since it varies according to the patient’s minute ventilation. When delivering oxygen through a Venturi mask, a
nominal FiO2, up to 60%, is delivered to the patient. However, it should be strengthened that FiO2 is nominal and not
actual. Indeed, Venturi mask has holes to prevent CO2 rebreathing and patient may potentially also re-breath part of
the exhaled air. Furthermore, if the inspiratory peak flow of
the patient exceeds the flow provided by the Venturi mask,
the patient breathes part of atmospheric air [31].
In ten healthy volunteers, Ritchie et al. have measured
the FiO2, end-tidal O2 and end-tidal CO2 from a hypopharyngeal catheter during HFNC at flow rates of 10, 20, 30, 40
and 50 L/min. During nose breathing at rest, the delivered
FiO2 was not affected by atmospheric air at flow >30 L/min;
when the inspiratory peak flow was increased with the exercise to an extent greater than the flow delivered by HFNC,
FiO2 significantly decreased under the prescribed concentration [21]. In exacerbated COPD patients, the mean inspiratory peak flow has been reported to be around 70 L/min and to
exceed 60 L/min in about 70% of the patients [34]. Therefore, HFNC use may guarantee a more stable FiO2, as compared to COT through nasal prongs, oxygen or Venturi mask.
3.2. Treatment Comfort
Patient comfort and device tolerance are two of the most
important determinants for NIV and treatment success [35,
36]. Breathing dry oxygen generates discomfort and pain
related to mouth, throat and airways dryness, particularly in
High Flow Through Nasal Cannula in COPD
Table 1.
Reviews on Recent Clinical Trials, 2019, Vol. 14, No. 4
251
Physiologic effects of HFNC reported in stable COPD.
Ref.
Airway
Pressure
Braunlich
et al. [43]
+
Respiratory RespiraEndEffort /
tory
Respiratory Intrinsic Tidal Expiratory Minute
Quality Expiratory
Comfort Dyspnea
PaCO2
of Life
Work of
Work
Rate
PEEP Volume
Time Ventilation
Lung
Breathing
Load
Volume
-
-
+
+
-
+
+
-
-
-
Fraser
et al. [44]
Pisani et al.
[33]
-
-
-
-
-
Vogelsinger et al.
[45]
Atwood
et al. [46]
+
-
-
-
-
=
=
=
Storgaard
et al. [47]
-
+
Nagata
et al. [48]
-
+
Biselli et al.
[49]
-
Cirio et al.
[50]
-
-
-
-
+
-
Modifications of physiologic parameters, compared to conventional oxygen therapy, in stable COPD patients. The sign “+” indicates and increment or improvement, “=” no modification and “-” a reduction, as compared to conventional oxygen therapy. PEEP, positive end-expiratory pressure; PaCO2, arterial partial pressure of carbon dioxide.
critically ill patients [37]. For this reason, clinical practice
guidelines recommend to humidify dry oxygen when administered at flow >4L/min [38]. HFNC is characterized by delivery of fully humidified inspired oxygen/air admixture,
which improves patients’ comfort and facilitates secretion
elimination [31]. Compared to COT, it has been shown that
HFNC improves comfort in a multicenter randomized controlled trial conducted in 105 hypoxemic patients after extubation [31], in 30 exacerbated COPD patients recovering
from an episode of exacerbation at NIV withdrawn [20] and
in 42 exacerbated COPD patients receiving HFNC or NIV
after extubation [39]. Of note, recently Mauri et al. have
reported that, in 40 patients with hypoxemic ARF, a high
(37°C) temperature worsened the patient’s comfort, compared to lower temperature (31°C) [40]. Nowadays, no studies have so far investigated the effects of different temperatures and/or flow rates on comfort in stable and/or exacerbated COPD patients.
3.3. HFNC in Stable COPD Patients
In COPD patients with severe chronic hypoxemia at rest
(PaO2 < 55mHg), or PaO2 ranging from 55 to 59 mmHg in
the presence of signs of Cor Pulmonale or hematocrit > 55%,
LTOT is indicated for at least 15 hours/day. LTOT has proven to improve survival rate [4, 41]; however, the treatment
compliance is hampered by a low tolerance of patients [42].
From literature research, we have identified 9 studies
dealing with HFNC in stable COPD patients (Table 1). The
risk of bias has been assessed in all studies and it is reported
in Fig. (2). It should be mentioned that the assessment of
performance bias (i.e., the blinding of participants and personnel with respect to the assigned treatment) is at high risk
due to the impossibility of treatment blinding.
Braunlinch et al. firstly have reported HFNC use in severe (GOLD C/D) COPD patients [43]; the authors have
assessed the modifications of generated mean nasopharyngeal pressure, breathing pattern, comfort and dyspnea at incremental flow rates (from 20 to 50 L/min). HFNC progressively increased the mean nasopharyngeal pressure from 0.92 ±
0.49 mbar (at 20 L/min) up to 3.01 ± 1.03 mbar (at 50
L/min) irrespective of the used nasal prongs size. Furthermore, compared to spontaneous breathing at room air, HFNC
reduced the respiratory rate, the minute ventilation, the respiratory work load (as assessed by the rapid shallow breathing pattern) and PaCO2, whereas increased by the 24% the
tidal volume at 50L/min. In all tested conditions, HFNC
guaranteed a good comfort and dyspnea relief [43].
In 30 COPD patients using LTOT over 15 hours/day,
Fraser et al. have shown that HFNC significantly reduced the
transcutaneous CO2, diminished the respiratory rate, prolonged the expiratory time and increased both the tidal vol-
252
Reviews on Recent Clinical Trials, 2019, Vol. 14, No. 4
Bruni et al.
Fig. (2). The graph depicts the review authors' judgments about each risk of bias item as percentages across all included studies conducted in
stable COPD patients.
ume and the end-expiratory lung volume, as opposed to COT
[44].
More recently, in 14 consecutive COPD patients, Pisani
et al. have reported that both HFNC and NIV significantly
reduced the respiratory rate and effort, prolonged the expiratory time and decreased dynamic intrinsic PEEP, as compared to spontaneous breathing [33]. Furthermore, both
HFNC and NIV slightly, though not significantly, decreased
PaCO2, as opposed to baseline [33].
In 77 COPD patients with the indication to LTOT, Vogelsinger et al. have applied in consecutive both COT and
HFNC for 60 minutes, with a 30-min wash out phase in between. Compared to COT, HFNC has been better tolerated
and reduced the FiO2 requirement and PaCO2, without modifications of lung volumes [45].
Atwood et al. have randomized 32 moderate-to-severe
stable COPD patients to receive COT or HFNC [46]. As
opposed to COT, HFNC reduced the respiratory rate without
any increase in tidal volume or PaCO2. Furthermore, HFNC
reduced the ventilatory effort in the absence of modifications
of PaCO2 or tidal volume, suggesting also a relevant wash
out effect of the upper airway and ventilatory efficiency improvement [46]. This study was limited by a short-term evaluation without the assessment of potential clinical benefits of
enhanced humidification, wash out effect and ventilatory
efficiency improvement [46].
In a prospective randomized controlled trial, 200 COPD
patients with the indication to LTOT have been randomized
to receive either COT or COT plus HFNC (at 20 L/min for at
least 8 hours/night) [47]. Compared to COT, HFNC significantly reduced the rate of exacerbation and hospitalization,
dyspnea and PaCO2 at 12 months, without modification of
the survival rate. Certain deterioration at 12 months of the
quality of life and exercise performance, measured through
6-minute walk test, was observed in patients receiving COT,
while not in those receiving HFNC [47].
HFNC has been also tested in stable COPD patients during sleep [48, 49]. In 29 COPD patients receiving LTOT,
Nagata et al. have assessed the efficacy and safety of 6weeks of domiciliary HFNC for at least 4 hours per night at
30-40 L/min [48]. Compared to COT only, HFNC significantly improved the quality of life and reduced PaCO2 without any severe HFNC-related adverse events [48]. In 12
COPD patients and in a control group of 6 smokers, Biselli
et al. have assessed HFNC effects (at 20 L/min) and COT (at
2 L/min) with respect to ventilation and work of breathing
during sleep [49]. Compared to spontaneous breathing in
room air, both COT and HFNC decreased the tidal volume
and the minute ventilation during NREM sleep; however, the
effect on PaCO2 was contradictory. If on one hand PaCO2
increased with COT, on the other it decreased in case of
HFNC treatment. In addition, COT did not reduce the work
of breathing, whereas HFNC decreased it by the 50% [49].
In 12 stable severe COPD patients, the effects of HFNC
have been assessed during a constant load exercise at the
75% of maximum workload achieved at a previous incremental exercise test on cycle-ergometer [50]. Compared to
breathing at room air, HFNC significantly increased the endurance time, the oxygenation during the exercise, while
diminished the dyspnea and the leg fatigue scores, as reported by patients [50].
The differences among studies in term of setting of
HFNC application, severity of the disease and assessed outcomes preclude us the possibility to conduct a pooled data
analysis. However, we have summarized the findings of all
the studies in Table 1. Of note, in the vast majority of the
selected studies HFNC has reduced the respiratory rate, the
work of breathing and the blood content of CO2, increased
the tidal volume, while improved the quality of life and
dyspnea. Further studies, properly designed and powered to
assess differences in clinical outcomes (rather than physiologic ones), are deemed necessary.
3.4. HFNC in Exacerbated COPD Patients
COPD exacerbations are complex events usually associated with increased airway inflammation, increased mucus
production and marked gas trapping. During exacerbation,
High Flow Through Nasal Cannula in COPD
Reviews on Recent Clinical Trials, 2019, Vol. 14, No. 4
253
Fig. (3). The graph depicts the review authors' judgments about each risk of bias item as percentages across all included studies conducted in
exacerbated COPD patients.
patients refer mainly worsening of dyspnea, increased sputum purulence and volume, cough and wheeze [4]. COPD
exacerbation can be classified as mild (when treated with
short-acting beta agonist bronchodilators [SABA] only),
moderated (when the patient requires hospitalization, SABA
and/or corticosteroids) and severe (when associated with
ARF) [4].
Hypercapnic ARF is present or develops in approximately 20% of hospitalized COPD patients, and it is an indicator
of increased risk of death [51]. Hypercapnic ARF establishes
when the respiratory work load exceeds the respiratory muscles pump capacity, and a rapid shallow breathing pattern
develops. Furthermore, dynamic hyperinflation also contributes to increase the respiratory work load, through the generation of intrinsic PEEP [51].
Nowadays, guidelines strongly recommend the use of
NIV with a high certainty of evidence, whenever hypercapnic ARF with acidosis is present [51]. A trial of NIV is also
recommended when the patients is considered to require endotracheal intubation and iMV, unless immediate deterioration [51]. In fact, NIV has been shown to improve gas exchange, reduce work of breathing and the need for intubation, decrease hospital length of stay and mortality [51].
Despite these advantages, NIV has been shown to suffer
of poor patient-ventilator interaction, which determines a
worsening of patient’s comfort and tolerance to the treatment
and its failure [52-59]. Although patient-ventilator asynchrony can be partially managed by optimizing ventilator
setting or using particular modes of ventilation [52-65], it
remains difficult to recognize such events by the sole ventilator waveform observation without the use of additional signals [66].
As opposed to NIV, HFNC is not characterized by the
drawback of patient-ventilator interaction and synchrony;
furthermore, some physiological mechanisms which could be
of clinical benefit in COPD patients have been reported in
this review. For this reason, an increasing amount of literature is exploring the possible role of HFNC in exacerbated
COPD patients with established hypercapnic ARF, at extubation or at NIV discontinuation.
From the literature research, we have identified 10 studies reporting the use of HFNC in exacerbated COPD patients
(Table 2). In particular, 4 case reports/case series have described HFNC use as an alternative to NIV, 2 studies have
compared HFNC to COT as first line oxygen treatment at
exacerbation, 3 studies have applied HFNC at exacerbated
COPD patients after extubation (2 against NIV and 1 against
COT) and, in the end, 1 study has compared HFNC to COT
at NIV withdrawal (Table 2). The risk of bias has been assessed in all studies and it is reported in Fig. (3). As for studies investigating the role of HFNC in stable patients, also
these studies suffer a high risk of performance bias due to the
unblinded designs.
The first HFNC applications in exacerbated COPD patients have been reported from 2014 as case reports [67-69]
or series [70]. In these patients, HFNC was successfully applied after NIV treatment failure due to poor tolerance of the
interface [67, 68, 70] or massive unmanageable air-leaks
[69]. In these few patients, HFNC further has improved gas
exchange [67-70], was well tolerated [67-70], significantly
reduced the apnea index (from 12.1 to 3.7 events/hour) and
the percentage time with SpO2 ≤90% (from 30.8 to 2.5%)
[67].
These preliminary data from case reports have opened the
possibility to assess the role of HFNC in exacerbated COPD
patients, as alternative treatment to NIV.
In a retrospective study, Kim et al. have assessed the feasibility to employ HFNC in 33 patients with hypercapnic
ARF admitted to ICU. Compared to the pre-treatment condition, HFNC significantly decreased PaCO2 at 1 hour, without
modifying oxygenation or respiratory rate [71]. In 2017,
Pilcher et al. prospectively have randomized 24 exacerbated
COPD patients to receive COT via nasal prongs and HFNC
at 35 L/min, in a cross-over design [72]. In with a study by
Kim et al. [71], HFNC slightly, though significantly, reduced
the transcutaneous CO2 tension, without significant and clinically relevant modifications of respiratory and heart rate and
SpO2 [72].
In a Chinese hospital, all COPD patients admitted in the
ICU requiring iMV have been randomized to receive NIV or
254
Reviews on Recent Clinical Trials, 2019, Vol. 14, No. 4
Table 2.
Ref.
Bruni et al.
Physiologic effects of HFNC reported in exacerbated COPD.
Setting
Sleep
Respiratory
ICU
Gas
Treatment
Related
Respiratory
Drive /
Heart Rate
Comfort Length of
Exchange Success HypoventilaRate
Work of
Stay
tion
Breathing
ReintubaMortality
tion Rate
Case report / case series
Okuda et al. Alternative to
[67]
NIV
+
+
Lepere et al. Alternative to
[68]
NIV
+
+
Alternative to
NIV
+
+
Pavlov et al. Alternative to
[70]
NIV
+
+
Plotnikow
et al. [69]
+
Retrospective study
Hypercapnic
Kim et al.
ARF, compared
[71]
to COT
+
=
Randomized controlled or cross-over trials
Hypercapnic
Pilcher et al.
ARF, compared
[72]
to COT
+
Zhang et al.
[73]
At extubation,
compared to
NIV
=
Di Mussi
et al. [19]
At extubation,
compared to
COT
=
Longhini
et al. [20]
At NIV withdrawal, compared to COT
=
Jing et al.
[39]
At extubation,
compared to
NIV
=
=
-
=
=
=
=
=
-
-
-
+
+
Modifications of physiologic parameters, compared to conventional oxygen therapy, in stable COPD patients. The sign “+” indicates and increment or improvement, “=” no modification and “-” a reduction, as compared to conventional oxygen therapy. ICU, intensive care unit; NIV, non-invasive ventilation; ARF, acute respiratory failure; COT, conventional
oxygen therapy.
HFNC after extubation [73]. HFNC was characterized by a
shorter ICU length of stay, as compared to COT. No differences were recorded between treatments in terms of gas exchange (apart of oxygenation slightly better in NIV), 28-days
reintubation rate and mortality [73].
In 14 COPD patients after extubation recovering from an
exacerbation episode, Di Mussi et al. firstly have investigated the effects of HFNC with respect to work of breathing and
gas exchange [19]. As compared to COT, HFNC significantly
decreased the work of breathing and the respiratory drive, as
assessed through the electrical activity of the diaphragm [19].
Similar findings have been also recently reported in a
randomized cross-over trial by our group. In 30 COPD patients recovering from an episode of exacerbation with indi-
cation to be weaned off from NIV, HFNC was compared
with COT and NIV with respect to gas exchange, diaphragm
function (as assessed by ultrasounds), respiratory rate, and
patient comfort [20]. PaCO2 and pH were not different between HFNC and COT. However, while the diaphragm activation and respiratory rate significantly increased with COT,
as compared to NIV, no modifications were shown during
HFNC. Furthermore, HFNC resulted in improved comfort
compared to both COT and NIV. Noteworthy, after NIV
discontinuation and at the end of the study protocol, 15 patients received COT and 15 HFNC, by chance. In the next 48
hours after NIV withdrawal, NIV was reinstituted in 47% of
patients receiving COT, while in 27% among those receiving
HFOT. However, these last findings have been beyond the
study aim and they must be considered with caution [20].
High Flow Through Nasal Cannula in COPD
Table 3.
Reviews on Recent Clinical Trials, 2019, Vol. 14, No. 4
255
Possible clinical scenarios and settings for the use of HFNC in COPD patients.
-
Stable COPD Patients
Exacerbated COPD Patients
Aim of treatment
1.
In alternative to COT
1.
2.
3.
4.
Settings
1.
2.
3.
4 to 7 hours/night
flow between 30 to 50 L/min
FiO2 set to guarantee a SpO2 between 88-94%
1.
2.
3.
In alternative di NIV in case of intolerance
In alternative to COT
After extubation
At NIV withdrawal
Continuous treatment till resolution of the condition
flow between 40 to 60 L/min (titrated according patient’s comfort)
FiO2 set to guarantee a SpO2 between 88-94%
COPD, Chronic Obstructive Pulmonary Disease; COT, conventional oxygen therapy; FiO2, inspired oxygen fraction; SpO2, peripheral oxygen saturation; NIV, non-invasive ventilation.
In the end, Jing et al. have randomized 42 exacerbated
COPD patients after extubation to receive NIV or HFNC
[39]. HFNC was not inferior to NIV in weaning COPD patients from iMV, with regard to gas exchange and vital signs.
Patients randomized to receive HFNC required less bronchoscopy for suction of secretions, as opposed to NIV; furthermore, HFNC and NIV did not differ in terms of time
spent under iMV, need for reintubation, ICU length of stay
and all cause of 28-days mortality. Of note, HFNC has been
reported to be more comfortable than NIV [39].
As for data regarding HFNC in stable COPD patients, we
could not conduct a pooled data analysis due to the heterogeneity among studies in term of setting of HFNC application, assessed outcomes and reason of HFNC treatment. Anyhow, these preliminary data open the possibility of application of HFNC as an alternative interface to COT or NIV for
COPD patients with exacerbation, in different clinical situations. However, further randomized controlled trials are
deemed to assess potential benefits on major clinical outcomes.
4. DISCUSSION
HFNC is increasingly used in the daily clinical practice,
in patients with hypoxemic ARF due to strong and growing
body of favorable evidences [1, 3]. In contrast, little is
known in HFNC use in those patients with hypercapnic
ARF, where no clear evidence of superiority of HFNC to
both COT and NIV still exists.
In stable severe hypoxemic COPD patients, COT is delivered at home to increase the blood oxygenation and resulting in an improved survival rate [4]; however, COT remains
affected by a low tolerance by patients, due to dryness of
compressed medical oxygen. HFNC provides heated and
humidified air-oxygen admixture, making oxygen therapy
more comfortable to patients. Furthermore, HFNC has been
shown to reduce the PaCO2 with a minor energy expenditure
cost by the respiratory muscles (i.e., reduced work of breathing and respiratory rate), to improve the quality of life and
exercise performance and to reduce dyspnea, as compared to
COT. The compliance of a patient to a prescribed therapy
strictly depends on comfort and tolerance to the treatment,
remarkably for medical devices such as oxygen therapy and
NIV [35]. In principles, the improved comfort and reduced
work of breathing, together with COPD symptoms relief,
would improve the adherence to the therapy. Despite these
physiological advantages, nowadays a clear evidence of
HFNC superiority against to COT still lacks in stable COPD
patients. Indeed, based on the current literature, domiciliary
HFNC may be safely used in stable COPD patients for 4 to 7
hours/day, during the night time, at a flow between 30 to 50
L/min and a FiO2 set to guarantee a SpO2 ranging between
88-94% (Table 3).
While in stable COPD patients, HFNC could be an alternative to the oxygen therapy, in exacerbated COPD with
hypercapnic ARF and respiratory acidosis its role may be
more complex, through fascinating. To date, guidelines
strongly recommend the use of NIV in exacerbated COPD
patients with respiratory acidosis [51]. In these patients, NIV
is most commonly applied in pneumatically-triggered and
cycled-off Pressure Support mode through a face mask [74].
However, this setting can be affected by discomfort to the
interface and poor patient-ventilator interaction and synchrony, potentially leading to NIV failure [52, 55, 57, 59].
Comfort improvement can be attempted through the use of
alternative interface (such as the helmet) [56, 75, 76]. Unfortunately, the helmet is characterized by a poor patientventilator interaction and pressurization performance [77].
Recent technical advances [78-81] and the use of proportional modes of ventilation based on the Electrical Activity of
the Diaphragm, so-called Neurally Adjusted Ventilatory Assist (NAVA) [63], have been shown to limit such drawbacks.
More recently, a specific setting of NAVA has been proposed to further improve pressurization and triggering performance in patients receiving iMV or NIV through both
helmet and mask [53, 57, 59]. All these advances have been
developed with the aim to improve patient’s comfort, and to
theoretically reduce the rate of treatment failure and need for
iMV. HFNC may potentially play a role of alternative treatment for those exacerbated COPD patients who failed NIV
due to poor treatment tolerance. In particular, HFNC may be
considered: 1) in case of respiratory acidosis, when NIV fails
for intolerance [67-70], 2) after extubation when NIV cannot
be used or is problematic [19, 39, 73], and 3) after NIV interruption at the resolution of the hypercapnic ARF, instead of
COT [20]. As opposed to NIV, HFNC cannot be affected by
a poor patient-ventilator interaction and synchrony; furthermore, HFNC is generally more comfortable to the NIV inter-
256
Reviews on Recent Clinical Trials, 2019, Vol. 14, No. 4
face or COT, providing heated and humidified gas admixture
[20]. Noteworthy, HFNC is also characterized by the ability
to reduce the respiratory drive and effort [19, 20], to a similar extent than NIV [20]. Although some trials are ongoing to
assess the potential benefits on patients’ clinical outcome
[82], today HFNC could be considered in the clinical practice in some situations for COPD patients. Based on the current literature on exacerbated COPD patients, HFNC should
be used only as an alternative interface in case of NIV failure
(to avoid intubation), or instead of COT. The applied settings
could consist in: 1) a flow rate between 40 to 60 L/min
(higher than in stable COPD), and titrated according patient’s comfort, and 2) a FiO2 set to guarantee a SpO2 ranging between 88-94%.
In the end, it should be mentioned that HFNC is easily
applied by physicians to the patients with a variety of diseases and conditions. Large randomized controlled trials, conducted in hypoxemic patients, have never reported any absolute contraindications to HFNC, except for those patients
whom NIV is contraindicated (such as severely alteration of
the consciousness, facial injury, unstable hemodynamics or
impaired airway patency). On the opposite, HFNC has the
advantage to not require a tight contact with the patient’s
face and therefore could be easily utilized in patients suffering
of claustrophobia, which usually do not tolerate NIV [83].
Bruni et al.
majority of the study is quite small, potentially generating
positive results which could not be confirmed in larger studies [84]. For this reason, we strongly believe that further
studies properly designed and powered to assess differences
in clinical outcomes (rather than physiologic ones) are
deemed necessary in both stable and exacerbated COPD patients.
CONCLUSION
HFNC may be advantageous either in stable and exacerbated COPD patients. In stable COPD patients, HFNC reduces the work of breathing, respiratory rate dyspnea and
PaCO2, prolongs the expiratory time, improves the respiratory work load, the quality of life and exercise performance. In
exacerbated COPD, HFNC reduces the respiratory drive to
an extent similar to NIV, while keeping similar gas exchange. It remains to clarify with proper randomized controlled trials whether these physiological benefits may translate into clinical outcomes improvement.
LIST OF ABBREVIATIONS
AH
=
Absolute Humidity
ARF
=
Acute Respiratory Failure
CO2
=
Carbon Dioxide
4.1. Strengths and Limitations of this Review
COPD
=
Chronic Obstructive Pulmonary Disease
This review has some strengths and limitations requiring
discussion.
COT
=
Conventional Oxygen Therapy
FiO2
=
Inspiratory Fraction of Oxygen
First of all, to our knowledge this is the first systematic
review which includes a comprehensive and systematic literature search on HFNC in COPD patients. Although a comprehensive narrative review on the potential physiological
benefits of HFNC in stable COPD patients exists [2], there is
no review today which summarize findings in both stable
and exacerbated COPD patients with respect to assessed
(mainly physiological) outcomes. Furthermore, the interest
in the use of HFNC in both stable and exacerbated COPD
patients is raised in the last few years, while more robust
evidence already exists in hypoxemic patients [3].
HFNC
=
High Flow Nasal Cannula
ICU
=
Intensive Care Unit
iMV
=
Invasive Mechanical Ventilation
LTOT
=
Long-Term Oxygen Therapy
NAVA
=
Neurally Adjusted Ventilatory Assist
NIV
=
Non-Invasive Ventilation
PaCO2
=
Arterial Partial Pressure of Carbon Dioxide
PaO2
=
Arterial Partial Pressure of Oxygen
Although a growing number of studies has been published, we could not conduct a pooled data analysis for several reasons. First of all, the vast majority of the studies assessed the effects of HFNC on different physiological outcomes, such as respiratory rate, respiratory drive, blood gases and comfort, rather than major clinical outcomes. It
should be mentioned however that physiological studies are
the solid ground to develop larger and well-targeted trials
aimed to assess the differences in clinical outcomes. Second,
as shown by risk of bias assessment, the quality of the studies is quite low, the number of the enrolled patients small
and the heterogeneity among population very high, which
preclude us the possibility to proceed with a further metaanalysis. Therefore, the application of GRADE methodology, to assess certainty in pooled estimates of effect, has not
been conducted. Third, the conclusions, which could be generated by the current literature, would be strongly affected by
weak evidence support. Indeed, the sample size of the vast
PaO2/FiO2 =
Ratio between Arterial Partial Pressure and
Inspiratory Fraction of Oxygen
PEEP
=
Positive End-Expiratory Pressure
RH
=
Relative Humidity
SABA
=
Short-Acting Beta Agonist
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
Dr. Navalesi’s research laboratory has received equipment and grants from Maquet Critical Care, Draeger and
High Flow Through Nasal Cannula in COPD
Intersurgical S.p.A. He also received honoraria/speaking fees
from Maquet Critical Care, Orionpharma, Philips, Resmed,
MSD and Novartis.Dr. Navalesi contributed to the development of the helmet Next, whose licence for patent belongs to
Intersurgical S.P.A., and receives royalties for that invention.
Dr. Longhini and Dr. Navalesi contributed to the development of a new device not discussed in the present study
whose patent is in progress (European Patent application
number EP20170199831). The remaining authors have
disclosed that they do not have any conflicts of interest.
Reviews on Recent Clinical Trials, 2019, Vol. 14, No. 4
[5]
[6]
[7]
ACKNOWLEDGEMENTS
Andrea Bruni was responsible for conception and design
of the study, the acquisition and interpretation of the data,
and for drafting and revising the article for final approval of
the version to be published. Eugenio Garofalo was responsible for conception and design of the study, the acquisition
and interpretation of the data, and for drafting and revising
the article for final approval of the version to be published.
Gianmaria Cammarota was responsible for conception and
design of the study, the interpretation of the data, and for
revising the article for final approval of the version to be
published. Paolo Murabito was responsible for conception
and design of the study, the interpretation of the data, and for
revising the article for final approval of the version to be
published. Marinella Astuto was responsible for conception
and design of the study, the interpretation of the data, and for
revising the article for final approval of the version to be
published. Paolo Navalesi was responsible for conception
and design of the study, the interpretation of the data, and for
revising the article for final approval of the version to be
published. Francesco Luzza was responsible for conception
and design of the study, the interpretation of the data, and for
revising the article for final approval of the version to be
published. Ludovico Abenavoli was responsible for conception and design of the study, the interpretation of the data,
and for revising the article for final approval of the version to
be published. Federico Longhini was responsible for conception and design of the study, the acquisition and interpretation of the data, and for drafting and revising the article for
final approval of the version to be published.
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