INVITED REVIEW SERIES:
NON-INVASIVE VENTILATION
SERIES EDITORS: AMANDA PIPER AND CHUNG-MING CHU
Benefits of non-invasive ventilation in acute hypercapnic
respiratory failure
VITTORIA COMELLINI,1 ANGELA MARIA GRAZIA PACILLI2 AND STEFANO NAVA1,2
1
Respiratory and Critical Care Unit, University Hospital St Orsola-Malpighi, Bologna, Italy; 2Department of Specialistic,
Diagnostic and Experimental Medicine (DIMES), Alma Mater Studiorum University of Bologna, Bologna, Italy
ABSTRACT
Non-invasive ventilation (NIV) with bilevel positive air-
way pressure is a non-invasive technique, which refers
to the provision of ventilatory support through the
patient’s upper airway using a mask or similar device.
This technique is successful in correcting hypoventila-
tion. It has become widely accepted as the standard
treatment for patients with hypercapnic respiratory fail-
ure (HRF). Since the 1980s, NIV has been used in inten-
sive care units and, after initial anecdotal reports and
larger series, a number of randomized trials have been
conducted. Data from these trials have shown that NIV
is a valuable treatment for HRF. This review aims to
explore the principal areas in which NIV can be useful,
focusing particularly on patients with acute HRF
(AHRF). We will update the evidence base with the goal
of supporting clinical practice. We provide a practical
description of the main indications for NIV in AHRF
and identify the group of patients with hypercapnic fail-
ure who will benefit most from the application of NIV.
Key words: hypercapnia, non-invasive ventilation, respiratory
acidosis, respiratory failure.
INTRODUCTION
The normal level of carbon dioxide (CO2) tension in
the arterial blood (PaCO2) results from the relationship
between the rate of CO2 production and the portion of
CO2 eliminated by the lung with alveolar ventilation.
Acute hypercapnic respiratory failure (AHRF) is more
commonly determined by a defect of this latter mecha-
nism (respiratory pump failure), when the respiratory
muscles do not provide sufficient alveolar ventilation to
maintain a normal arterial PaCO2.1 A rapid elevation of
PaCO2 leads to a drop in arterial blood pH as a conse-
quence of the lowering of HCO3_/PaCO2 ratio.
Correspondence: Stefano Nava, Respiratory and Critical Care
Unit, University Hospital St Orsola-Malpighi, Via G. Massarenti
9, Bologna 40138, Italy. Email: stefanava@gmail.com
Received 3 September 2018; invited to revise 19 September,
19 and 28 October, and 15 November 2018; revised 9, 22 and
30 October, and 18 November 2018; accepted 9 December 2018.
© 2019 Asian Pacific Society of Respirology
AHRF is classically considered a main feature of
advanced chronic obstructive pulmonary disease
(COPD), and the role of non-invasive ventilation (NIV)
for its treatment is established.2 However, an imbalance
between the increased elastic and resistive load and
the reduced capacity of the respiratory pump is not a
unique feature of acute exacerbation of COPD
(AECOPD). Many other diseases may lead to AHRF,
and therefore NIV has been also used in a wide range
of other conditions associated with acidosis and hyper-
capnia, despite most of the studies having been con-
ducted in patients with COPD (see Table 1).3
This review aims to discuss what is known from the
present literature and to summarize the main indica-
tions of NIV in AHRF in a practical way.
ACUTE EXACERBATION OF COPD
NIV is considered the standard of care in the manage-
ment of AHRF secondary to AECOPD4 both in patients
with and without previous chronic hypercapnia.
Since the late 1980s, NIV has been used in intensive
care units (ICU) and emergency departments. In the
first randomized controlled trial, Brochard et al.5
showed NIV significantly reduced the need for endotra-
cheal intubation (ETI) when compared to standard
medical treatment among patients admitted to an ICU
with AECOPD. The frequency of complications was sig-
nificantly lower in the NIV group and the mean hospi-
tal stay significantly shorter. The in-hospital mortality
rate was also significantly reduced with NIV. A subse-
quent study confirmed NIV was associated with
reduced rates of ETI and mortality.6
Conti et al.7 compared NIV and invasive mechanical
ventilation (IMV) in 49 patients with an AECOPD who
failed standard medical treatment. In these very sick
patients, NIV was proven to be non-inferior than ETI
and IMV. Moreover, in those patients who could be
managed successfully with NIV, there was an advan-
tage both in terms of reduction in ICU stay, readmis-
sions to hospital in the following year and need for de
novo long-term oxygen therapy.
The application of NIV in general wards has been
also widely investigated in a number of studies. In the
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doi: 10.1111/resp.13469
2 V Comellini et al.
Table 1 Indications for NIV in acute hypercapnic
respiratory failure
1 Acute exacerbation of COPD
2 Cardiogenic pulmonary oedema
3 Obesity and obesity hypoventilation syndrome
4 Weaning from invasive mechanical ventilation
5 Prevention of post-extubation failure in those patients
previously intubated
6 Chest wall diseases and neuromuscular diseases
7 Palliative care and do-not-intubate patients
8 Miscellaneous (very old patients, community-acquired
pneumonia and bridge to transplantation)
COPD, chronic obstructive pulmonary disease; NIV,
non-invasive ventilation.
largest one, it was confirmed that delivery of NIV in
general ward is feasible.8 In this multicentre UK trial
comparing NIV with standard therapy, early institution
of NIV reduced treatment failure and halved hospital
mortality. From a post hoc subgroup analysis, data
emerged suggesting a worse outcome in patients with
pH 7.30. Thus, sicker, more acidotic patients should be
monitored more closely in order to avoid delays in
intubation.
In a prospective pilot cohort study conducted by
Fiorino et al. in a non-‘highly protected’ environment
in a medical ward of a rural hospital,9 NIV produced
similar improvements in arterial blood gases not only
in patients with mild, but also with severe forms of
respiratory acidosis. The favourable results of this pro-
spective study, and of another retrospective one10 may
be related to the long-term experience of the staff with
NIV and the improved technology of ventilators and
interfaces, compared with Plant et al.’s study.8
The benefits of NIV and its non-inferiority to stan-
dard therapy have been confirmed in a large number
of other randomized controlled trial (RCT) in many dif-
ferent settings, in different countries and healthcare
systems.11
Several large surveys showed that the use of NIV has
become widespread in the treatment of AECOPD in
Europe and in the United States.12–14
Nowadays, NIV can be delivered safely in any dedi-
cated setting, ranging from emergency departments,
medical units to high-dependency and ICU. Of note,
however, NIV should be performed by adequately
trained staff with the availability of appropriate moni-
toring facilities because despite increasing experience
with this technique, the rate of NIV failure remains
high at 20% and 30% in patients with COPD admitted
to ICU, especially in those patients with severe dys-
pnoea.15,16 A successful outcome is highly dependent
on accurate patient selection and among patients with
COPD the severity of hypercapnia and/or acidosis after
initiation of NIV is a major predictor of NIV failure.17–19
As remarked in recent ATS/ERS guidelines,4 strong
evidence supports the use of NIV in patients who
develop AHRF (pH ≤ 7.35, PaCO2 > 45 mm Hg) due to
AECOPD.
Within this group, we can identify less severely ill
patients with a pH of 7.25–7.35. For these patients, NIV
could be useful to prevent the progression of acidosis
© 2019 Asian Pacific Society of Respirology
and the requirement of ETI and mechanical ventilation
(MV). For the more severely ill patients, typically with a
pH < 7.25, instead of being a preventive tool, NIV can
represent an alternative to ETI. There is no lower limit
of pH below which a trial of NIV is inappropriate; how-
ever, the lower the pH, the greater the risk of failure,
and patients must be very closely monitored with rapid
access to ETI and IMV if not improving. Therefore, a
cautious trial of NIV can be considered, unless the
patient is immediately deteriorating. When compared
to IMV, successful NIV reduces the duration of ICU
and hospital stay, the number of hospital readmissions
in the subsequent year,7 ventilator-associated pneumo-
nia and the requirement for tracheostomy.20 Coma has
been classically described as a contraindication to NIV,
but the clinically favourable response of a subset
patients with hypercapnic encephalopathy has made
this statement questionable.21–23
Conversely, NIV is not recommended for patients
with AECOPD and hypercapnia who do not have
acidosis.4,24–28 Hence, in these patients with hypercap-
nia but no acidosis, the pillars of treatment are medical
therapy and, most importantly, correct titration of oxy-
gen, targeted to a saturation of 88–92%,29 as hyper-
oxygenation is a cause of acidosis and hypercapnia.30
In recent years, significant emphasis has been placed
on the possible use of new techniques, such as high-
flow nasal cannula (HFNC). HFNC delivers a mix of air
and oxygen with an inspired oxygen fraction (FiO2)
ranging between 0.21 and 1.0, and with a range of pos-
sible gas flows (1–60 L/min).The gas undergoes 100%
humidification and is heated to approximately normal
body temperature. Over the last 10 years, HFNC have
had widespread uptake in the adult population, due to
its versatility and ease of use. The main fields of appli-
cation of HFNC are still the treatment of acute hypox-
aemic respiratory failure, that is not a specific topic of
this review,31–33 or prevention of post-extubation respi-
ratory failure.34 The HFNC seems more effective than
conventional oxygen therapy and non-inferior to NIV
in most studies conducted among hypoxaemic patients.
Another issue is that of hypercapnic patients. However,
HFNC has also been recently proposed in hypercapnic
acute and chronic respiratory failure. HFNC can pro-
vide several benefits in these populations, such as
maintenance of a constant and accurate FiO2, genera-
tion of a positive end-expiratory pressure (PEEP),
reduction of the anatomical dead space, improvement
of mucociliary clearance and reduction in the work of
breathing.35,36 It is presumed that these benefits may
help in reducing or at least in getting under control
alveolar hypoventilation, making HFNC a valid support
to use with NIV or as an alternative to it for the less
severe patients (i.e. for patients who are hypercapnic,
but not acidotic). However, this matter will have to be
further discussed and confirmed in future RCT. During
an episode of AHRF, Lee et al. in a prospective obser-
vational trial compared the effectiveness of HFNC and
NIV and did not find any difference in intubation rate
and 30-day mortality between the two groups.37 Cer-
tainly, most of the studies showed that HFNC is consis-
tently better tolerated by patients than NIV, as mask
intolerance is one of the main causes of NIV failure,
leading to ETI. Optimization of the treatment includes
Respirology (2019)
NIV and hypercapnic respiratory failure
the appropriate selection of the interfaces (material, fit,
size and type) in order to minimize complications such
as decubitus injuries and claustrophobia. Anxiety and
delirium are important issues in critical care environ-
ment, and their occurrence is high both in ICU38 and in
respiratory intensive care.39 Delirium is associated with
increased mortality especially in patients undergoing
NIV, as demonstrated by Chan et al., who reported an
augmented risk for the occurrence of early death of 4.4
in this group of patients.40
Judicious use of sedation during NIV could be a
valuable option. However, although widely used in
clinical practice, sedation during NIV has been investi-
gated only in a few studies.41–47 The current limited
data available suggest that it could be safe and feasible.
Remifentanil or dexmedetomidine could have the most
suitable overall profile, while benzodiazepines should
generally be avoided, as well as haloperidol or atypical
antipsychotics.48,49 However, more widespread applica-
tion and the determination of the ‘ideal’ sedative or
analgesic drug to be used during NIV, as well as the
best route and modalities of administration, should
await the results of further RCT.
CARDIOGENIC PULMONARY OEDEMA
Cardiogenic pulmonary oedema (CPE) frequently leads
to acute respiratory failure (ARF), sometimes associ-
ated with hypercapnia, mostly in patients with a preex-
isting chronic lung disease (CLD).50 Around 20–50% of
patients with severe CPE have hypercapnia and this is
considered as a marker of severity associated with a
higher risk of intubation.51 In general, in this subset of
patients, the rate of NIV success is very high (96%).52
Continuous positive airway pressure (CPAP) and NIV
represent the first line of treatment together with stan-
dard medical therapy in acute CPE.
Nevertheless, CPAP can not be considered a ‘real’
form of MV, as it does not provide support during the
inspiratory phase, but a constant positive pressure is
applied to raise functional residual capacity and open
flooded alveoli. NIV or so-called bilevel ventilation
(i.e. the combination of inspiratory pressure and expi-
ratory pressure) is, on the other hand, a ‘real’ form of
ventilation, and therefore theoretically more appropri-
ate when the respiratory pump is failing.
In the subset of patients with hypercapnia, a multi-
centre study comparing NIV with standard oxygen, the
former decreased the need for intubation, and was
associated with a reduction in hospital mortality, and
similar rates of myocardial infarction.53
When a head-to-head comparison between CPAP
and NIV was performed, NIV accelerated the improve-
ment of ARF compared to CPAP but did not affect pri-
mary clinical outcomes (i.e. death and intubation)
either in overall population or in subgroups of patients
with hypercapnia or those with high B-type natriuretic
peptide.54
Similar results were obtained by Bellone et al. dem-
onstrating NIV was as effective as CPAP in the treat-
ment of patients with CPE and hypercapnia, but did
not improve resolution time.55
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3
In 2008, Grey et al. published the largest multicentre
trial, in which >1000 patients were randomized to
CPAP, NIV or standard oxygen therapy. This trial found
physiological improvement in the CPAP and bilevel
NIV groups compared with the standard group, but no
difference in intubation rate or mortality at 7 and
30 days. Although a pH of <7.35 was one of the inclu-
sion criteria, only <20% of the patients were affected by
a chronic respiratory disorder.56
Five systematic reviews subsequent to this investiga-
tion concluded CPAP and NIV are equivalent and supe-
rior to standard oxygen in reducing intubation rate and
mortality, but still did not clarify which one of the two
techniques should be preferentially used in patients
with hypercapnia.57–61 Hence, either NIV or CPAP is
recommended for patients with ARF due to CPE, even
in the pre-hospital setting.4,62 In case of hypercapnia,
NIV could theoretically be the preferred choice for its
greater action on alveolar hypoventilation.
Moreover, clinicians should be aware that patients
with CPE presenting with severe hypercapnia
(PaCO2 > 60 mm Hg) may require particular attention.
Contou et al. demonstrated that among patients treated
for severe CPE and having no identified underlying
CLD, severe hypercapnia at admission correlates with a
longer duration of NIV without an increase in intuba-
tion rate.63
OBESITY AND OHS
Respiratory involvement in obese patients is complex
and includes pulmonary abnormalities, impairment of
central respiratory control and sleep-related breathing
disorders.64 Although obesity is frequent in patients
with COPD, asthma and sleep apnoea–hypopnea syn-
drome (SAHS), a minority of obese subjects develop
obesity hypoventilation syndrome (OHS), defined by a
body mass index (BMI) >30 kg/m2 and chronic alveolar
hypoventilation leading to daytime hypercapnia.64
There is a paucity of data regarding the use of NIV in
obese patients, most of which arises from case series,
often retrospective, with limited patient numbers.65–67
Rabec et al. showed that patients with AHRF and
OHS can be successfully treated with NIV, as most of
them improved PaCO2 and avoided ETI.68 Similar
results were obtained by Duarte et al., who demon-
strated that in 50 morbidly obese patients with AHRF,
NIV avoided ETI in the majority of cases.69 In addition,
hospital mortality for the IMV and NIV failure group
was higher compared with those successfully managed
with NIV.
Bry et al. showed that among 77 obese adults admit-
ted in an ICU because of ARF, subjects with the most
severe obesity or who experienced the most difficult
initial ventilation were at higher risk of receiving long-
term NIV.70 However, NIV at home was effective and
well tolerated.
Not all the patients with OHS, undergoing AHRF,
require long-term NIV, as a significant proportion can
be managed with CPAP while others can be weaned
completely.71
Carillo et al. compared outcomes in patients with
AHRF due to OHS or COPD, who were treated with
© 2019 Asian Pacific Society of Respirology
4 V Comellini et al.
NIV.72 Patients with OHS had less late NIV failure,
lower hospital mortality and higher 1-year survival.
Among patients with COPD, obesity was associated
with less late NIV failure and hospital readmission.
Interestingly, both COPD and OHS patients were venti-
lated using the same settings, while in clinical practice
the two groups commonly receive different levels of
inspiratory and expiratory pressures.
Despite the large clinical use of NIV in AHRF due to
OHS, we are still lacking RCT, and therefore no recom-
mendation has been given by the ERS/ATS guidelines.4
WEANING FROM IMV
Prolonged intubation and MV are related to high mor-
bidity and mortality,73,74 and a strategy to accelerate the
process of weaning is expected to improve patient
prognosis and to shorten the ICU length of stay.
In the majority of cases, withdrawal of MV is possible
immediately after resolution of the underlying prob-
lems responsible for ARF. However, there is a group of
ventilated patients, namely those with a preexisting
respiratory disease and persisting hypercapnia, who
require more gradual and longer withdrawal of MV.
In patients with ventilator-dependent hypercapnia
and COPD, NIV has been shown to be as effective as
IMV in reducing inspiratory effort and improving arte-
rial blood gases.75,76 Patients who failed a T-piece trial
were randomized to either extubation, with immediate
application of NIV, or continued weaning with the
endotracheal tube in place. Overall, this study showed
that when NIV is used as a weaning technique, the like-
lihood of weaning success is increased, while the dura-
tion of MV and ICU stay decreased.
A second RCT was conducted on patients with CLD,
intubated during an episode of ARF.77 This study
pointed out a shorter duration of IMV in the groups
weaned non-invasively, although no differences were
found in ICU or hospital stay or 3-month survival.
Further studies were performed over the following
years. Burns et al.78 identified 16 RCT enrolling 994 par-
ticipants overall, mostly with COPD. Compared with
conventional weaning, NIV was associated with a sig-
nificant decrease in mortality, ventilator-associated
pneumonia, ICU and hospital length of stay and total
duration of MV, especially in the subset of patients with
a preexisting CLD.
Considering these findings, recent guidelines4 sug-
gest the application of NIV to facilitate weaning from
MV in patients with AHRF.
PREVENTION OF POST-EXTUBATION
FAILURE IN THOSE PATIENTS
PREVIOUSLY INTUBATED
Post-extubation failure is a major clinical problem in
ICU.79 Two randomized trials have been performed to
assess whether NIV is effective in preventing the occur-
rence of post-extubation failure in patients at risk, most
of them affected by hypercapnia after the removal of
endotracheal tube.80,81 Both studies showed that the
groups treated with NIV had a lower rate of
© 2019 Asian Pacific Society of Respirology
reintubation; furthermore, a post hoc analysis of the
latter trial showed that ICU mortality was also reduced
in the subgroup of patients with hypercapnia treated
with NIV. A subsequent RCT performed in this specific
condition has confirmed this important result.82
Two smaller single-centre trials also randomized
patients to receive NIV or standard treatment after
planned extubation.83,84 Khilnani et al. enrolled patients
with COPD only and found no differences regarding
intubation rate and ICU and hospital lengths of stay.
Ornico et al. enrolled mostly patients with AECOPD
and found a significant reduction in the rates of reintu-
bation and deaths in the NIV group.
In conclusion, promptly initiated NIV for at least
48 h in selected ‘at-risk’ patients may prevent post-
extubation respiratory failure, especially in those
patients with persistent hypercapnia.
CHEST WALL DISEASES AND
NEUROMUSCULAR DISEASES
In patients with neuromuscular diseases (NMD) and
chest wall diseases (CWD), the decrease in respiratory
muscle strength (resulting in ineffective alveolar venti-
lation), altered rib cage compliance and weakness of
expiratory muscles (leading to inadequate clearance of
airway secretions) are causes of chronic hypercapnic
respiratory failure (HRF), that during exacerbations,
may lead to potentially life-threatening problems.85
The NMD can be classified into two main categories,
according to the clinical onset of AHRF: (i) slowly pro-
gressive NMD with acute exacerbation of chronic respi-
ratory failure and (ii) rapidly progressive NMD. Motor
neurone diseases, spinal muscular atrophy (SMA) and
inherited myopathies (i.e. Duchenne muscular dystro-
phy) are the most frequent slowly progressive NMD,
while myasthenia gravis (MG), Guillain–Barré syn-
drome (GBS) and inflammatory myopathies are the
most common rapidly progressive, and potentially
reversible, NMD.86
Treatment of chronic ventilatory failure with noctur-
nal NIV combined with mechanically assisted coughing
is the standard of care in adults and children with HRF
secondary to slowly progressive disorders and CWD.87
Very little is known about the use of NIV during an
episode of AHRF, despite the fact that NMD account
for about 10% of ICU admissions.88 Among patients
with neuromuscular respiratory failure, those without a
known diagnosis before ICU admission have poorer
outcomes.89
A recent Cochrane review90 found no RCT using NIV
to treat an acute exacerbation in NMD and RTD
patients.
Flandreau et al.91 described the outcome of 87 NMD
patients experiencing their first AHRF episode requir-
ing ICU admission. Among patients with hereditary dis-
eases and acquired diseases, respectively, the rates of
NIV use during the ICU stay were 82% and 63% and
the intubation rates were 30% and 56%. At hospital dis-
charge, 46% of the patients were on NIV and 29% had
tracheotomy.
Vianello et al.92 showed that NIV combined with
mini-tracheotomy decreased the mortality and ICU stay
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NIV and hypercapnic respiratory failure
versus IMV in 14 patients with hypercapnic ARF due to
slowly progressive NMD.
An observational study found that NIV was effective
in avoiding tracheal intubation in 79% of the 17 NMD
patients enrolled.93
Only three small studies have been published on the
use of NIV in patients with MG,94–96 and only two case
reports in patients with GBS.97,98 NIV was shown to pre-
vent intubation in patients with myasthenic crisis, but
this effect was observed only in patients without
hypercapnia.
While ‘chronic’ NIV is the standard of care in CWD
and NMD patients, we are still lacking RCT
during AHRF.
PALLIATIVE CARE AND DNI PATIENTS
NIV may be used as a ceiling treatment, merely as a
palliative tool to relieve dyspnoea, in critically ill
patients with end-stage disease. A European survey
carried out in several respiratory ICU found that up to
22% of those admitted to hospital in a terminal phase
of their disease, received this treatment.99
Palliative care usually concerns cancer patients, but
also refers to subjects with end-stage chronic respira-
tory failure. Chronic hypercapnia and dyspnoea are
typical features of the advanced phase of these respira-
tory diseases and breathlessness also occurs in these
terminal patients as a consequence of AECOPD or car-
diac failure.100
Patients and their families expect symptomatic relief
of devastating symptoms, such as dyspnoea, pain, anxi-
ety and fear of death.
Despite the best possible medical management,
almost all the patients with end-stage cancer or respira-
tory diseases experience breathlessness, and NIV can
help relieve their suffering and eventually to die
peacefully.101–103 A multicentre RCT showed a signifi-
cantly greater reduction in breathlessness, especially in
the hypercapnic subgroup of patients, when NIV was
compared to standard oxygen therapy.102 Interestingly,
the authors also showed that NIV might reduce the
dose of morphine necessary to palliate dyspnoea,
maintaining better cognitive function. Overall, NIV had
a similar rate of acceptance by patients compared with
oxygen therapy (60%).102 Hence, NIV has become part
of the therapeutic armamentarium of palliative
care.103,104 However, although it is considered a ‘non-
invasive’ technique, the use of NIV in a palliative care
setting may be controversial. First, this is because the
patient may not tolerate NIV well, with undesirable
side effects such as skin lesions, irritation of the eyes
and claustrophobia. Second, it is thought that NIV may
unduly delay death.105,106 Therefore, the decision to
stop or continue NIV in this scenario is not based on
an ‘objective’ physiological variable, but only on the
patient’s wishes.
A particular issue for using NIV as a palliative tool is
that of patients bearing a do-not-intubate (DNI) order
(patients with life-threatening ARF who refuse intuba-
tion/tracheostomy).6,107,108 In this respect, NIV may be
used palliatively but also with a ‘curative’ aim. The lat-
ter would be the case in a reversible cause of ARF,
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5
despite these patients frequently experiencing severe
respiratory acidosis and hypercapnia with associated
encephalopathy, which are potential predictors of NIV
failure. We lack RCT in this scenario, but in observa-
tional studies, the use of NIV in patients with ‘DNI’ was
associated, at least in some subsets of patients (COPD
and congestive heart failure), with a surprisingly high
(>30–60%) hospital survival and a 3-month quality of
life equivalent to patients treated with NIV and having
no limitation placed on support.109
The use of NIV is becoming increasingly popular in
patients with DNI or as a palliative tool in terminally ill
patients, but clinicians should have very clear goals
regarding therapy in these patients.
MISCELLANEOUS (VERY OLD
PATIENTS, CAP AND BRIDGE TO
TRANSPLANTATION)
The proportion of elderly people among hospitalized
patients, including ICU admissions, is rapidly growing
in developed countries. According to recent epidemio-
logical studies, very old patients (i.e. those older than
80 years) represent 10–15% of ICU admissions.110,111
A large observational study on 1019 patients needing
ventilatory support showed that 376 (37%) received
NIV. Among them, 163 (16%) very old patients
(>80 years) received ventilatory support, with 60% of
them managed with NIV compared with 32% of youn-
ger patients. Hospital mortality was higher in very old
than in younger patients but interestingly it did not dif-
fer when NIV was used for AHRF due to CPE or acute-
on-chronic respiratory failure. The 6-month mortality
was 51% in very old patients, 67% for patients with
‘DNI’ and 77% in case of NIV failure and ETI.112
There are a few other smaller observational studies,
showing that NIV may be useful to treat AHRF in old
or very old patients, with an average mortality rate of
<40%.113–115
The only RCT in these patients was performed by
Nava et al. enrolling 82 patients older than 75 years.116
During an episode of AHRF in old patients with a pre-
existing CLD, the use of NIV was associated with a
lower proportion of patients meeting ETI criteria, a
higher survival rate and faster resolution of respiratory
distress when compared with standard treatment. The
use of NIV as a rescue therapy was associated with a
lower mortality rate compared with ETI.
Concerning de novo ARF, recent guidelines4 were
unable to offer a recommendation on the use of NIV in
this area. Despite this, some RCT in patients with
community-acquired pneumonia (CAP) have demon-
strated that NIV is associated with a reduced need for
ETI.117–121However, in real life, potential harms of NIV
exist. For example, patients with pneumonia who
received NIV were 56% more likely to require intuba-
tion than patients with COPD who received NIV, and
no survival benefits were observed in Medicare patients
comparing NIV and IMV.122–125
The treatment of respiratory failure due to pneumo-
nia with NIV may also lead to greater mortality than
other modes of non-invasive oxygen supplementation
such as HFNC.31 Interestingly, only one study has
© 2019 Asian Pacific Society of Respirology
6 V Comellini et al.
considered the use of NIV in CAP and AHRF in patients
with a preexisting CLD.119 Fifty-five patients were ran-
domized to NIV or standard treatment. Subgroup anal-
ysis showed that patients randomized to NIV had a
reduced need for intubation and a better 2-month sur-
vival. However, this was not confirmed among those
patients with ‘pure hypoxia’, suggesting that in AHRF
associated with CAP, NIV may be of some benefit.
Many patients with cystic fibrosis (CF) develop respi-
ratory failure from progressive airway obstruction and
bronchiectasis and when the disease becomes more
severe, hypercapnia may ensue.126 At this stage, NIV
may focus on alleviating both the symptomatic and
physiological effects of respiratory failure.1,127 Patients
with CF or bronchiectasis may suffer AHRF during an
exacerbation of moderate to severe disease, or indeed
without any identified specific acute cause. In this pop-
ulation, NIV ameliorates dyspnoea and avoids ETI and
its complications.128–131 Moreover NIV could sustain life
until more definitive life prolonging treatment could be
offered; NIV as a ‘bridge’ to transplant has become
routine at centres capable of performing lung trans-
plant for CF.129,131–133 However, to date, only modest
evidence supports the use of NIV in patients with CF,
and there were no long-term data on its safety or
efficacy.
CONCLUSIONS
When respiratory pump failure occurs, leading to
AHRF, NIV is a therapeutic option of paramount
importance.
Large data sets from RCT conducted in populations
of hypercapnic patients demonstrate that the principal
indications are AECOPD and CPE; however, benefits
have also been shown when NIV is applied to OHS and
obese patients, who develop hypercapnia. NIV is indi-
cated during weaning from MV and for prevention of
post-extubation failure in patients at risk of developing
HRF. A further field of application of this technique is
NMD and CWD, not only in the chronic, but also in
the acute setting. Another point of note is the use of
NIV in palliative care and in patients with a DNI order.
In these patients, NIV has proved to be a valuable tool
for relieving symptoms and sometimes for correcting
AHRF. In CF, future RCT evaluating a larger population
for a longer period of time are need to assess the effi-
cacy and the role of NIV as a treatment of AHRF or as
a ‘bridge’ to transplant.
Disclosure statement
S.N. has received research grants from Fisher and Paykel and is
on the advisory board for Philips and Breas.
The Authors
S.N. is Professor of Respiratory Medicine, Department of Experi-
mental, Diagnostic and Specialty Medicine – DIMES, Alma Mater
Studiorum University of Bologna, and Head of the Division of
Respiratory and Critical Care Unit, St Orsola-Malpighi Hospital,
Bologna. His interests include MV (including non-invasive),
COPD exacerbation, weaning from MV, organization and eco-
nomic analysis of respiratory ICU, respiratory muscle
© 2019 Asian Pacific Society of Respirology
(electromyographie, electrical stimulation of the diaphragm and
mechanics) and pharmacology of the ‘acute’ patient. V.C. is Phy-
sician at the Division of Respiratory and Critical Care Unit, St
Orsola-Malpighi Hospital, Bologna, Diagnostic and Specialty
Medicine – DIMES, Alma Mater Studiorum, University of Bolo-
gna. Her interests are respiratory failure, MV (invasive and non-
invasive), weaning from MV, lung ultrasounds, respiratory mus-
cle and infections of the respiratory tract. A.M.G.P. is Assistant
Professor of Respiratory Medicine, Department of Experimental,
Diagnostic and Specialty Medicine – DIMES, Alma Mater Stu-
diorum University of Bologna, and Attending Physician at the
Division of Respiratory and Critical Care Unit, St Orsola-Malpighi
Hospital, Bologna. Her interests are causes and treatment of
respiratory failure.
Abbreviations: AECOPD, acute exacerbation of COPD; AHRF,
acute HRF; ARF, acute respiratory failure; CAP, community-
acquired pneumonia; CF, cystic fibrosis; CLD, chronic lung
disease; CO2, carbon dioxide; CPAP, continuous positive airways
pressure; CPE, cardiogenic pulmonary oedema; CWD, chest wall
diseases; DNI, do not intubate; ETI, endotracheal intubation;
FiO2, inspired oxygen fraction; GBS, Guillain–Barré syndrome;
HFNC, high-flow nasal cannula; HRF, hypercapnic respiratory
failure; ICU, intensive care unit; IMV, invasive MV; MG,
myasthenia gravis; MV, mechanical ventilation; NIV, non-
invasive ventilation; NMD, neuromuscular disease; OHS, obesity
hypoventilation syndrome; PaCO2, CO2 tension in the arterial
blood; RCT, randomized controlled trial.
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